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WO2023177894A1 - Polythérapie comprenant un inhibiteur de mat2a et un agent antimétabolite - Google Patents

Polythérapie comprenant un inhibiteur de mat2a et un agent antimétabolite Download PDF

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Publication number
WO2023177894A1
WO2023177894A1 PCT/US2023/015548 US2023015548W WO2023177894A1 WO 2023177894 A1 WO2023177894 A1 WO 2023177894A1 US 2023015548 W US2023015548 W US 2023015548W WO 2023177894 A1 WO2023177894 A1 WO 2023177894A1
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WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
cancer
combination therapy
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PCT/US2023/015548
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English (en)
Inventor
Claire L. NEILAN
Marcus Michael FISCHER
Kimberline Yang GERRICK
Jenny Leigh LARAIO
Anthony Mazurek
Geeta Sharma
Original Assignee
Ideaya Biosciences, Inc.
Glaxosmithkline Intellectual Property (No.4) Limited
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Publication of WO2023177894A1 publication Critical patent/WO2023177894A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • Cancer is a leading cause of death throughout the world.
  • a limitation of prevailing therapeutic approaches, e.g., chemotherapy and immunotherapy, is that their cytotoxic effects are not restricted to cancer cells and adverse side effects can occur within normal tissues.
  • Methionine adenosyltransferase 2A is an enzyme that utilizes methionine (Met) and adenosine triphosphate (ATP) to generate s-adenosyl methionine (SAM).
  • SAM is a primary methyl donor in cells used to methylate several substrates including DNA, RNA, and proteins.
  • One methylase that utilizes SAM as a methyl donor is protein arginine N- methyltransferase 5 (PRMT5). While SAM is required for PRMT5 activity, PRMT5 is competitively inhibited by 5’methylthioadenosine (MTA). Since MTA is part of the methionine salvage pathway, cellular MTA levels stay low in a process initiated by methylthioadenosine phosphorylase (MTAP).
  • MTAP methylthioadenosine phosphorylase
  • MTAP is located at a locus on chromosome 9 that is often deleted in the cells of patients with cancers from several tissues of origin including central nervous system, pancreas, esophageal, bladder and lung (cBioPortal database). Loss of MTAP results in the accumulation of MTA making MTAP-deleted cells more dependent on SAM production, and thus MAT2A activity, compared to cells that express MTAP. In an shRNA cell-line screen across approximately 400 cancer cell lines, MAT2A knockdown resulted in the loss of viability in a larger percentage of MTAP-deleted cells compare to MTAP WT cells (see McDonald et. al. 2017 Cell 170, 577-592).
  • MAT2A inhibitors may provide a novel therapy for cancer patients including those with MTAP-deleted tumors.
  • Anti-metabolites and anti-folates are utilized for the treatment of cancer. These agents interfere with one-carbon metabolism which is involved with both the folate and methionine cycles.
  • the by-products of the metabolism of folate and methionine are utilized for essential functions such as nucleotide biosynthesis and methylation reactions (see Newman et. Al. Br J Cancer. 2017 Jun 6; 116(12): 1499-1504).
  • a combination product comprising a methionine adenosyltransferase II alpha (MAT2A) inhibitor and an antimetabolite.
  • the combination product is useful for the treatment of a variety of cancers, including solid tumors.
  • the combination product is also useful for the treatment of a variety of diseases or disorders treatable by inhibiting MAT2A.
  • the combination product is also useful for treating MTAP- deficient tumors.
  • a combination of a MAT2A inhibitor and an antimetabolite is provided herein.
  • the antimetabolite is an antifolate.
  • a pharmaceutical composition comprising a therapeutically effective amount of a methionine adenosyltransferase II alpha (MAT2A) inhibitor and a second pharmaceutical composition comprising a therapeutically effective amount of an antimetabolite.
  • the antimetabolite is an antifolate.
  • provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and an antimetabolite, thereby treating the cancer in the subject.
  • the antimetabolite is an antifolate.
  • provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and an antimetabolite, together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject.
  • the antimetabolite is an antifolate.
  • the cancer is characterized by a reduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, absence of MTAP gene, reduced function of MTAP protein, reduced level or absence of MTAP protein, MTA accumulation, or combination thereof.
  • MTAP methylthioadenosine phosphorylase
  • provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a MAT2A inhibitor and a therapeutically effective amount of a pharmaceutical composition comprising an antimetabolite, thereby treating the cancer in the subject.
  • the antimetabolite is an antifolate.
  • a disease or disorder treatable by inhibiting MAT2A in a subject in need thereof comprising administering to the subject a combination comprising a methionine adenosyltransferase II alpha (MAT2A) inhibitor and an antimetabolite, thereby treating the disease or disorder in the subject.
  • MAT2A methionine adenosyltransferase II alpha
  • the antimetabolite is an antifolate.
  • the disease or disorder is cancer.
  • provided herein are methods of treating a disease or disorder treatable by inhibiting MAT2A in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and an antimetabolite, together with at least a pharmaceutically acceptable carrier, thereby treating the disease or disorder in the subject.
  • the antimetabolite is an antifolate.
  • the disease or disorder is cancer.
  • the MAT2A inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables of Formula (I) are defined below.
  • the MAT2A inhibitor is Compound A having the following structural formula:
  • the MAT2A inhibitor is Compound A1 having the following structural formula:
  • MAT2A inhibitors for use in the combination therapy described herein are described in WO 2020/123395 (PCT/US19/65260).
  • the generic and specific compounds described in the patent application are incorporated herein by reference and can be used to treat cancer as described herein.
  • the antimetabolite is an antifolate.
  • the antifolate is pemetrexed (Compound B) having the following structural formula:
  • Compound B or a pharmaceutically acceptable salt and/or hydrate thereof.
  • the chemical name for pemetrexed is (2S)-2-( ⁇ 4-[2-(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl ⁇ amino)pentanedioic acid.
  • “Pemetrexed,” or “Compound B” also includes pharmaceutically acceptable salts and/or hydrates thereof.
  • Compound B is pemetrexed disodium.
  • Compound B is pemetrexed disodium heptahydrate (also known as Alimta®).
  • the antifolate is 5-fluorouracil (Compound C) having the following structural formula:
  • the antifolate is capecitabine (also known as Xeloda® and referred to herein as Compound D) having the following structural formula:
  • Compound D or a pharmaceutically acceptable salt thereof.
  • the chemical name for capecitabine is pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4- yl]carbamate.
  • Figure 1 shows the efficacy of Compound A and Compound B in the RT-112/84 human bladder tumor cell line.
  • Figure 2 shows the summary of efficacy of Compound A and Compound B in the RT112/84 human bladder tumor cell line.
  • Figure 3 shows the anti- tumor efficacy of Compound A and Compound C in CTG- 0707 gastric cancer patient-derived xenografts (PDX).
  • Figure 4 shows the efficacy of Compound A and Compound B or Compound C in the NCI-H838 human NSCLC xenograft.
  • Figure 5 shows plasma s-adenosyl methionine on day 5 from NCI-H838 human NSCLC xenograft.
  • Figure 6 shows tumor s-adenosyl methionine on day 5 from NCI-H838 human NSCLC xenograft.
  • Figure 7 shows Pemetrexed (Compound B) single agent growth inhibition across six MTAP-deficient cell lines.
  • Figure 8 shows Excess over Bliss Synergy of Compound A and Pemetrexed (Compound B) combinations across six MTAP-deficient cell lines.
  • Figure 9 shows the efficacy of Compound A and Compound B in the LXFA737 NSCLC patient-derived xenograft (PDX).
  • Figures 10A-10M show the growth inhibition of Compound A and Compound B in 13 MTAP-deficient cell lines.
  • Figures 11 A-11 M show the Loewe Synergy of Compound A and Compound B in 13 MTAP-deficient cell lines.
  • a combination therapy comprising a methionine adenosyltransferase II alpha (MAT2A) inhibitor, or a pharmaceutically acceptable salt thereof, and an antimetabolite, or a pharmaceutically acceptable salt thereof.
  • the combination therapy is useful for the treatment of a variety of cancers.
  • the combination therapy is useful for the treatment of any number of MAT2A-associated diseases.
  • the combination therapy is useful for the treatment of a disease or disorder treatable by inhibiting MAT2A.
  • MTAP is an essential enzyme for the salvage pathway of adenosine synthesis
  • MTAP -deficient tumors are hypothesized to be sensitive to antifolate agents such as pemetrexed, due to dual blocking of the de novo and salvage pathways of adenosine synthesis.
  • MTAP gene deficiency creates vulnerability to anti-folate therapy in urothelial bladder carcinoma. Cancer Res 1 July 2019; 79) (13 Supplement)
  • Chen et al. demonstrated that both in an in vitro and in vivo settings, MTAP-deleted bladder cell lines or tumor models were more sensitive to pemetrexed than MTAP-WT models.
  • a MAT2A inhibitor to pemetrexed in the MTAP-deleted setting should further reduce DNA synthesis as a result of the reduction in SAM synthesis (a key component of the folate cycle), arising from inhibition of MAT2A.
  • the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.
  • the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ⁇ 20% or ⁇ 10%, including ⁇ 5%, ⁇ 1%, and ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.”
  • the terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps. It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format.
  • combination refers to either a fixed combination in one dosage unit form, or non-fixed combination in separate dosage forms, or a kit of parts for the combined administration where two or more therapeutic agents may be administered independently, at the same time or separately within time intervals.
  • combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure.
  • administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of active ingredients or in separate formulations (e.g., capsules and/or intravenous formulations) for each active ingredient.
  • administration also encompasses use of each type of therapeutic agent in a sequential or separate manner, either at approximately the same time or at different times.
  • the active ingredients are administered as a single formulation or in separate formulations
  • the drugs are administered to the same patient as part of the same course of therapy.
  • the treatment regimen will provide beneficial effects in treating the conditions or disorders described herein.
  • treating refers to inhibiting a disease; for example, inhibiting a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (/.e., arresting further development of the pathology and/or symptomology) or ameliorating the disease; for example, ameliorating a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (/.e., reversing the pathology and/or symptomology) such as decreasing the severity of the disease.
  • the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of the combination therapy provided herein to prevent some or all of the symptoms associated with the disorder or disease.
  • the term “patient,” “individual,” or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and marine mammals. Preferably, the patient, subject, or individual is human.
  • the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein a parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts described herein include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts discussed herein can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used.
  • pharmaceutically acceptable salt is not limited to a mono, or 1 :1, salt.
  • “pharmaceutically acceptable salt” also includes bis-salts, such as a bis-hydrochloride salt. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • composition refers to a mixture of at least one compound with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition facilitates administration of the composition to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
  • the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound disclosed herein, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of a compound disclosed herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. Other additional ingredients that may be included in the pharmaceutical compositions are known in the art and described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.
  • single formulation refers to a single carrier or vehicle formulated to deliver therapeutically effective amounts of both therapeutic agents to a patient.
  • the single vehicle is designed to deliver a therapeutically effective amount of each of the agents, along with any pharmaceutically acceptable carriers or excipients.
  • the vehicle is a tablet, capsule, pill, or a patch. In other embodiments, the vehicle is a solution or a suspension.
  • MAT2A inhibitor means an agent that modulates the activity of MAT2A or inhibits the production of S-adenosylmethionine (SAM) by methionine adenosyltransferase 2A (MAT2A).
  • SAM S-adenosylmethionine
  • antimetabolite includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, and folic acid antagonists such as pemetrexed.
  • the combination of agents described herein may display a synergistic effect.
  • the term “synergistic effect” or “synergy” as used herein, refers to action of two agents such as, for example, a MAT2A inhibitor and an antimetabolite, producing an effect, for example, slowing the symptomatic progression of cancer or symptoms thereof, which is greater than the simple addition of the effects of each drug administered by themselves.
  • a synergistic effect can be calculated, for example, using suitable methods such as the Sigmoid-Emax equation (Holford, N. H. G. and Scheiner, L. B., Clin. Pharmacokinet. 6: 429-453 (1981 )), the equation of Loewe additivity (Loewe, S.
  • a combination therapy comprising a therapeutically effective amount of a MAT2A inhibitor and an antimetabolite.
  • a “therapeutically effective amount” of a combination of agents i.e., a MAT2A inhibitor and an antimetabolite is an amount sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorders treated with the combination.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon (i.e. C 1-6 means one to six carbons) atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms (i.e. C 3-6 means three to six carbons).
  • Alkyl can include any number of carbons, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 .
  • alkyl groups inlcude methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like. It will be recognized by a person skilled in the art that the term “alkyl” may include “alkylene” groups.
  • Amino means a -NH 2 .
  • Cycloalkyl means a monocyclic monovalent hydrocarbon radical of three to six carbon atoms (e.g., C 3-6 cycloalkyl) which may be saturated or contains one double bond. Cycloalkyl can include any number of carbons, such as C 3-6 , C 4-6 , and C 5-6 , Partially unsaturated cycloalkyl groups have one or more double in the ring, but cycloalkyl groups are not aromatic. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • Halo means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one to five halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., -CH 2 CI, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 2 , and the like.
  • haloalkyl groups can have any suitable number of carbon atoms, such as C 1-6 .
  • a combination product comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and an antimetabolite, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • This combination product is also referred to herein as a combination therapy.
  • the combination product is useful for the treatment of a variety of cancers, including solid tumors.
  • the combination product is useful for the treatment of any number of MAT2A-associated diseases.
  • the combination product is useful for the treatment of a disease or disorder treatable by inhibiting MAT2A.
  • the combination product is useful for treating MTAP- deficient tumors.
  • a combination of a MAT2A inhibitor and an antimetabolite is provided herein.
  • the antimetabolite is an antifolate.
  • the disclosure provides MAT2A inhibitors.
  • the MAT2A inhibitor is a compound or a pharmaceutically acceptable salt thereof of Formula (I): wherein
  • X is C or N
  • R 3 is halo, C 1-6 haloalkyl or C 3-6 cycloalkyl
  • R 2 is -NR 4 R 5 ;
  • R 4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 1 is phenyl, wherein phenyl is substituted with 0-2 halo.
  • X in Formula (I) and subembodiments thereof is C. In an embodiment, X in Formula (I) and subembodiments thereof is N. In still another embodiment, R 3 in formula (I) and subembodiments thereof is halo or C 1-6 haloalkyl. In an embodiment, R 3 in formula (I) and subembodiments thereof is halo. In an embodiment, R 3 in formula (I) and subembodiments thereof is C 1-6 haloalkyl. In an embodiment, R 3 in formula (I) and subembodiments thereof is C 3-6 cycloalkyl. In an
  • R 3 in formula (I) and subembodiments thereof is chloro, fluoro, bromo, -CH 2 CI, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , or -CF(CH 3 ) 2 .
  • R 3 in formula (I) and subembodiments thereof is chloro or -CF 3 .
  • R 3 in formula (I) and subembodiments thereof is chloro.
  • R 3 in formula (I) and subembodiments thereof is -CF 3 .
  • R 4 in formula (I) and subembodiments thereof is H. In an embodiment, R 4 in formula (I) and subembodiments thereof is C 1-3 alkyl. In an embodiment, R 4 in formula (I) and subembodiments thereof is methyl, ethyl, propyl, or isopropyl.
  • R 5 in formula (I) and subembodiments thereof is H. In an embodiment, R 5 in formula (I) and subembodiments thereof is C 1-3 alkyl. In an embodiment,
  • R 5 in formula (I) and subembodiments thereof is methyl, ethyl, propyl, or isopropyl.
  • R 5 in formula (I) and subembodiments thereof is C 3-6 cycloalkyl.
  • R 2 in formula (I) and subembodiments thereof is -NH 2 , - NHC 1-3 alkyl, or -N(Ci-3alkyl)2. In an embodiment, R 2 in formula (I) and subembodiments thereof is NH 2 , -NHMe, or -N(Me)2. In an embodiment, R 2 in formula (I) and subembodiments
  • R 20 thereof is NH 2 .
  • R 2 in formula (I) and subembodiments thereof is -NHMe.
  • R 1 in formula (I) and subembodiments thereof is unsubstituted phenyl. In an embodiment, R 1 in formula (I) and subembodiments thereof is phenyl substituted with 1 halo. In an embodiment, R 1 in formula (I) and subembodiments thereof is phenyl substituted 1 halo selected fluoro and chloro. In an embodiment, R 1 in
  • formula (I) and subembodiments thereof is phenyl substituted chloro.
  • R 1 in formula (I) and subembodiments thereof is phenyl substituted 2 halo.
  • the MAT2A inhibitor is selected from the group consisting of a compound from Table 1 , or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor is Compound A:
  • the MAT2A inhibitor is Compound A1 having the following structural formula:
  • the antimetabolite is an antifolate.
  • the antifolate is selected from the group consisting of a compound in Table 2. Table 2 or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • a combination product comprising Compound A or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • Compound B is pemetrexed disodium.
  • Compound B is pemetrexed disodium heptahydrate (also known as Alimta®).
  • a combination product comprising Compound A, or a pharmaceutically acceptable salt thereof, and Compound C, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising Compound A, or a pharmaceutically acceptable salt thereof, and Compound D, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising Compound A1 , or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • Compound B is pemetrexed disodium.
  • Compound B is pemetrexed disodium heptahydrate.
  • a combination product comprising Compound A1 , or a pharmaceutically acceptable salt thereof, and Compound C, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising Compound A1 , or a pharmaceutically acceptable salt thereof, and Compound D, or a pharmaceutically acceptable salt thereof.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a MAT2A inhibitor and administering to the subject a therapeutically effective amount of an antimetabolite, thereby treating the cancer in the subject.
  • the antimetabolite is an antifolate.
  • provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a combination comprising a MAT2A inhibitor and an antimetabolite, together with at least a pharmaceutically acceptable carrier, thereby treating the cancer in the subject.
  • the antimetabolite is an antifolate.
  • the cancer is characterized by a reduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, absence of MTAP gene, reduced function of MTAP protein, reduced level or absence of MTAP protein, MTA accumulation, or combination thereof.
  • MTAP methylthioadenosine phosphorylase
  • provided herein are methods of treating cancer in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a MAT2A inhibitor and a therapeutically effective amount of a pharmaceutical composition comprising an antimetabolite, thereby treating the cancer in the subject.
  • the antimetabolite is an antifolate.
  • the antimetabolite is an antifolate.
  • the MAT2A inhibitor is Compound A.
  • the MAT2A inhibitor is Compound A1.
  • the antifolate is Compound B.
  • the antifolate is Compound C.
  • the antifolate is Compound D.
  • provided is a combination of Compound A and Compound B for the manufacture of a medicament.
  • provided is a combination of Compound A and Compound C for the manufacture of a medicament.
  • a combination of a MAT2A inhibitor and an antimetabolite for the treatment of cancer is provided.
  • the antimetabolite is an antifolate.
  • the MAT2A inhibitor is a compound of Formula (I).
  • the MAT2A inhibitor is Compound A.
  • the MAT2A inhibitor is Compound A1.
  • the antifolate is Compound B.
  • the antifolate is Compound C.
  • the antifolate is Compound D.
  • provided is a combination of Compound A and Compound B for the treatment of cancer.
  • provided is a combination of Compound A and Compound C for the treatment of cancer.
  • the MAT2A inhibitor is a compound or a pharmaceutically acceptable salt thereof of Formula (I): wherein the variables are defined supra.
  • the MAT2A inhibitor is selected from the group consisting of a compound from Table 1 , or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor is Compound A or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor is Compound A1 or a pharmaceutically acceptable salt thereof.
  • the antimetabolite is an antifolate.
  • the antifolate is selected from the group consisting of a compound in Table 2, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • the antifolate is Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • Compound B is pemetrexed disodium.
  • Compound B is pemetrexed disodium heptahydrate.
  • the antifolate is Compound C, or a pharmaceutically acceptable salt thereof.
  • the antifolate is Compound D, or a pharmaceutically acceptable salt thereof.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • Compound B is pemetrexed disodium.
  • Compound B is pemetrexed disodium heptahydrate.
  • provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound C, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound D, or a pharmaceutically acceptable salt thereof.
  • a method of treating bladder cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • provided herein is a method of treating gastric cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound C, or a pharmaceutically acceptable salt thereof.
  • a method of treating non-small cell lung cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • a method of treating non-small cell lung cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and administering to the subject a therapeutically effective amount of Compound C, or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor is a compound of Formula (I). In one embodiment, the MAT2A inhibitor is a compound in Table 1. In one embodiment, the MAT2A inhibitor is Compound A. In one embodiment, the MAT2A inhibitor is Compound A1. In an embodiment, the antimetabolite is an antifolate. In one embodiment, the antifolate is Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof. In an embodiment, Compound B is pemetrexed disodium. In another embodiment, Compound B is pemetrexed disodium heptahydrate. In one embodiment, the antifolate is Compound C, or a pharmaceutically acceptable salt thereof. In one embodiment, the antifolate is Compound D, or a pharmaceutically acceptable salt thereof.
  • a product containing a MAT2A inhibitor and an antimetabolite as a combined preparation for simultaneous, separate, or sequential use in treating cancer in a subject.
  • the MAT2A inhibitor is a compound of Formula (I).
  • the MAT2A inhibitor is a compound in Table 1.
  • the MAT2A inhibitor is Compound A.
  • the MAT2A inhibitor is Compound A1.
  • the antimetabolite is an antifolate.
  • the antifolate is Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • Compound B is pemetrexed disodium.
  • Compound B is pemetrexed disodium heptahydrate.
  • the antifolate is Compound C, or a pharmaceutically acceptable salt thereof.
  • the antifolate is Compound D, or a pharmaceutically acceptable salt thereof.
  • the cancer is selected from the group consisting of leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, anal cancer, stomach cancer, colon cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin lymphoma, gastric cancer, esophagogastric cancer, esophageal cancer, malignant peripheral nerve sheath tumor, and mesothelioma.
  • the cancer is mesothelioma. In an embodiment, the cancer is non-small cell lung cancer. In another embodiment, the cancer is nonsquamous non-small cell lung cancer. In one embodiment, the cancer is cancer of the colon or rectum. In an embodiment, the cancer is adenocarcinoma of the colon or rectum. In an embodiment, the cancer is breast cancer. In an embodiment, the cancer is adenocarcinoma of the breast. In an embodiment, the cancer is gastric cancer. In an embodiment, the cancer is gastric adenocarcinoma. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is pancreatic adenocarcinoma. In an embodiment, the cancer is bladder cancer.
  • the cancer is characterized as being MTAP-null.
  • the cancer is characterized as being MTAP-deficient.
  • the cancer is a solid tumor. In still another embodiment, the cancer is a MTAP-deleted solid tumor. In still another embodiment, the cancer is a metastatic MTAP-deleted solid tumor.
  • the cancer is metastatic.
  • the cancer is a solid malignant tumor.
  • the cancer is MTAP-deficient lung or MTAP- deficient pancreatic cancer, including MTAP-deficient NSCLC or MTAP-deficient pancreatic ductal adenocarcinoma (PDAC) or MTAP-deficient esophageal cancer.
  • MTAP-deficient lung or MTAP- deficient pancreatic cancer including MTAP-deficient NSCLC or MTAP-deficient pancreatic ductal adenocarcinoma (PDAC) or MTAP-deficient esophageal cancer.
  • the cancer is a tumor having an MTAP gene deletion.
  • the cancer is a solid tumor or a haematological cancer.
  • the tumor is deficient in MTAP.
  • the tumor is normal in its expression of MTAP.
  • the cancer is NSCLC, mesothelioma, squamous carcinoma of the head and neck, salivary gland tumors, urothelial cancers, sarcomas, or ovarian cancer.
  • the cancer is NSCLC, esophagogastric and pancreatic cancers.
  • the cancer is bladder cancer or gastrointestinal cancer.
  • the cancer is characterized by a reduction or absence of MTAP gene expression, absence of MTAP gene, reduced function of MTAP protein, reduced level or absence of MTAP protein, MTA accumulation, or combination thereof.
  • the cancer is characterized by a reduction or absence of MTAP gene expression.
  • the cancer is characterized by reduced function of MTAP protein.
  • the cancer is characterized reduced level or absence of MTAP protein.
  • the cancer is characterized by MTA accumulation.
  • the cancer is a tumor having a GNAQ gene mutation.
  • the cancer is a tumor having a GNA11 gene mutation.
  • the cancer is a tumor having PRKC fusions.
  • the MAT2A inhibitor and the antimetabolite are in separate dosage forms.
  • the MAT2A inhibitor and the antimetabolite are in the same dosage form.
  • the treatment comprises administering the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the antimetabolite, or a pharmaceutically acceptable salt thereof, at substantially the same time. In yet another embodiment, the treatment comprises administering the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the antimetabolite, or a pharmaceutically acceptable salt thereof, at different times.
  • the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof is administered to the subject, followed by administration of the antimetabolite, or a pharmaceutically acceptable salt thereof.
  • the antimetabolite, or a pharmaceutically acceptable salt thereof is administered to the subject, followed by administration of MAT2A inhibitor, or a pharmaceutically acceptable salt thereof.
  • the method comprises administering to the subject in need thereof a MAT2A inhibitor.
  • the method comprises administering to the subject in need thereof an antimetabolite.
  • the antimetabolite is an antifolate.
  • the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the antimetabolite, or a pharmaceutically acceptable salt thereof are administered orally.
  • the cancer to be treated is selected from the group consisting of leukemia, glioma, melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, anal cancer, stomach cancer, colon cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin lymphoma, gastric cancer, esophagogastric cancer, esophageal cancer, malignant peripheral nerve sheath tumor, and mesothelioma.
  • a MAT2A inhibitor or a pharmaceutically acceptable salt thereof, and an antimetabolite, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof, for use in therapy.
  • the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the antimetabolite, or a pharmaceutically acceptable salt thereof are for use in the treatment of cancer in a subject in need thereof.
  • Exemplary lengths of time associated with the course of the treatment methods disclosed herein include: about one week; about two weeks; about three weeks; about four weeks; about five weeks; about six weeks; about seven weeks; about eight weeks; about nine weeks; about ten weeks; about eleven weeks; about twelve weeks; about thirteen weeks; about fourteen weeks; about fifteen weeks; about sixteen weeks; about seventeen weeks; about eighteen weeks; about nineteen weeks; about twenty weeks; about twenty-one weeks; about twenty-two weeks; about twenty-three weeks; about twenty four weeks; about seven months; about eight months; about nine months; about ten months; about eleven months; about twelve months; about thirteen months; about fourteen months; about fifteen months; about sixteen months; about seventeen months; about eighteen months; about nineteen months; about twenty months; about twenty one months; about twenty-two months; about twenty-three months; about twenty-four months; about thirty months; about three years; about four years; and about five years.
  • the method involves the administration of a therapeutically effective amount of a combination or composition comprising compounds provided herein, or pharmaceutically acceptable salts thereof, to a subject (including, but not limited to a human or animal) in need of treatment (including a subject identified as in need).
  • the treatment includes co-administering the amount of the MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and the amount of the antimetabolite, or a pharmaceutically acceptable salt thereof.
  • the amount of the MAT2A inhibitor or a pharmaceutically acceptable salt thereof and the amount of antimetabolite or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form.
  • the amount of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and the amount of antimetabolite or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.
  • the treatment can include administering the amount of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and the amount of antimetabolite or a pharmaceutically acceptable salt thereof at substantially the same time or administering the amount of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and the amount of antimetabolite or a pharmaceutically acceptable salt thereof at different times.
  • the amount of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and/or the amount of antimetabolite or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of MAT2A inhibitor or a pharmaceutically acceptable salt thereof and antimetabolite or a pharmaceutically acceptable salt thereof is administered alone, but which amounts are effective in combination.
  • the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof are in a single formulation or unit dosage form.
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof are in a separate formulations or unit dosage forms.
  • the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound C, or a pharmaceutically acceptable salt thereof.
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound C, or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form.
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound C, or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.
  • the treatment includes co-administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound D, or a pharmaceutically acceptable salt thereof.
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound D, or a pharmaceutically acceptable salt thereof are in a single formulation or unit dosage form.
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound D, or a pharmaceutically acceptable salt thereof are in a separate formulations or unit dosage forms.
  • the treatment can include administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or the amount of Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof is administered at dosages that would not be effective when one or both of Compound A, or a pharmaceutically acceptable salt thereof, and Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof, is administered alone, but which amounts are effective in combination.
  • the treatment can include administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or the amount of Compound C, or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of Compound A, or a pharmaceutically acceptable salt thereof, and Compound C, or a pharmaceutically acceptable salt thereof, is administered alone, but which amounts are effective in combination.
  • the treatment can include administering the amount of Compound A, or a pharmaceutically acceptable salt thereof, and the amount of Compound
  • the amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or the amount of Compound D, or a pharmaceutically acceptable salt thereof is administered at dosages that would not be effective when one or both of Compound A, or a pharmaceutically acceptable salt thereof, and Compound D, or a pharmaceutically acceptable salt thereof, is administered alone, but which amounts are effective in combination.
  • a pharmaceutical composition comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, an antimetabolite, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof, and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of a MAT2A inhibitor or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of antimetabolite or a pharmaceutically acceptable salt thereof and/or a hydrate thereof is provided.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of a MAT2A inhibitor or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of an antimetabolite or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • the MAT2A inhibitor is a compound or a pharmaceutically acceptable salt thereof of Formula (I): wherein the variables are defined supra.
  • the MAT2A inhibitor is selected from the group consisting of a compound from Table 1 , or a pharmaceutically acceptable salt thereof.
  • the antimetabolite is an antifolate.
  • the antifolate is selected from the group consisting of a compound in Table 2, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • the MAT2A inhibitor is Compound A:
  • the MAT2A inhibitor is Compound A1 :
  • the antifolate is Compound B: or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • Compound B is pemetrexed disodium.
  • Compound B is pemetrexed disodium heptahydrate.
  • the antifolate is Compound C:
  • the antifolate is Compound D, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound C, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound D, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 , or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 , or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound C, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A1 , or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound D, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; Compound C, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; Compound D, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A1, or a pharmaceutically acceptable salt thereof; Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A1, or a pharmaceutically acceptable salt thereof; Compound C, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a therapeutically effective amount of Compound A1, or a pharmaceutically acceptable salt thereof; Compound D, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is for use in the treatment of cancer in a patient.
  • the pharmaceutical composition is for use in the treatment of a solid tumor in a patient.
  • the pharmaceutical composition is for use in the treatment of a solid malignant tumor in a patient.
  • the cancer is MTAP-deficient lung or MTAP- deficient pancreatic cancer, including MTAP- deficient NSCLC or MTAP-deficient PDAC or MTAP-deficient esophageal cancer.
  • the cancer is a solid tumor or a haematological cancer.
  • the cancer is NSCLC, mesothelioma, squamous carcinoma of the head and neck, salivary gland tumors, urothelial cancers, sarcomas, or ovarian cancer.
  • the cancer is NSCLC, esophagogastric and pancreatic cancers.
  • the cancer is bladder cancer or gastrointestinal cancer.
  • the cancer is bladder (urothelial) cancer or gastrointestinal cancer.
  • the cancer is bladder cancer.
  • the cancer is urothelial cancer.
  • the cancer is gastrointestinal cancer.
  • the pharmaceutical composition is for use in the treatment of mesothelioma in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of non-small cell lung cancer in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of nonsquamous non-small cell lung cancer in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of colon cancer in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of rectal cancer in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of colon or rectal adenocarcinoma of the colon or rectum in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of breast cancer in a patient.
  • the pharmaceutical composition is for use in the treatment of breast adenocarcinoma in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of gastric cancer in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of gastric adenocarcinoma in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of pancreatic cancer in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of pancreatic adenocarcinoma in a patient. In an embodiment, the pharmaceutical composition is for use in the treatment of bladder cancer in a patient.
  • compositions or pharmaceutical combination comprising the compounds disclosed herein, together with a pharmaceutically acceptable carrier.
  • MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and antimetabolite, or a pharmaceutically acceptable salt thereof are in the same formulation.
  • MAT2A inhibitor and antimetabolite are in separate formulations.
  • the formulations are for simultaneous or sequential administration.
  • Administration of the combination includes administration of the combination in a single formulation or unit dosage form, administration of the individual agents of the combination concurrently but separately, or administration of the individual agents of the combination sequentially by any suitable route.
  • the dosage of the individual agents of the combination may require more frequent administration of one of the agent(s) as compared to the other agent(s) in the combination. Therefore, to permit appropriate dosing, packaged pharmaceutical products may contain one or more dosage forms that contain the combination of agents, and one or more dosage forms that contain one of the combination of agents, but not the other agent(s) of the combination.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical doctor e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of pain, a depressive disorder, or drug addiction in a patient.
  • the compounds provided herein are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions provided herein comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.
  • the optimum ratios, individual and combined dosages, and concentrations of the drug compounds that yield efficacy without toxicity are based on the kinetics of the active ingredients’ availability to target sites, and are determined using methods known to those of skill in the art.
  • Routes of administration of any of the compositions discussed herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • the preferred route of administration is oral.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions are not limited to the particular formulations and compositions that are described herein. For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gel caps.
  • compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.
  • the present disclosure provides a kit for treating cancer comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and an antimetabolite, or a pharmaceutically acceptable salt thereof.
  • the kit comprises a pharmaceutical product comprising a pharmaceutical composition comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent; and a pharmaceutical composition comprising an antimetabolite, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • the kit comprises a pharmaceutical composition comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof; an antimetabolite, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.
  • kits are provided.
  • the kit includes a sealed container approved for the storage of pharmaceutical compositions, the container containing one of the above-described pharmaceutical compositions.
  • the sealed container minimizes the contact of air with the ingredients, e.g. an airless bottle.
  • the sealed container is a sealed tube.
  • An instruction for the use of the composition and the information about the composition are to be included in the kit.
  • the compounds of the combination can be dosed on the same schedule, whether by administering a single formulation or unit dosage form containing all of the compounds of the combination, or by administering separate formulations or unit dosage forms of the compounds of the combination.
  • the kit contains a formulation or unit dosage form containing all of the compounds in the combination of compounds, and an additional formulation or unit dosage form that includes one of the compounds in the combination of agents, with no additional active compound, in a container, with instructions for administering the dosage forms on a fixed schedule.
  • kits provided herein include prescribing information, for example, to a patient or health care provider, or as a label in a packaged pharmaceutical formulation.
  • Prescribing information may include for example efficacy, dosage and administration, contraindication and adverse reaction information pertaining to the pharmaceutical formulation.
  • kits provided herein can be designed for conditions necessary to properly maintain the components housed therein (e.g., refrigeration or freezing).
  • a kit can contain a label or packaging insert including identifying information for the components therein and instructions for their use (e.g., dosing parameters, clinical pharmacology of the active ingredient(s), including mechanism(s) of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.).
  • Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package.
  • Labels or inserts can include manufacturer information such as lot numbers and expiration dates.
  • the label or packaging insert can be, e.g., integrated into the physical structure housing the components, contained separately within the physical structure, or affixed to a component of the kit (e.g., an ampule, syringe or vial).
  • the present disclosure includes:
  • a combination product comprising a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and an antimetabolite, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • the MAT2A inhibitor of embodiment 1 is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor of embodiment 1 or 2 is selected from the group consisting of a compound in Table 1 , or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor of embodiment 3 is Compound A, or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor of any one of the embodiments 1 to 3 is Compound A1 , or a pharmaceutically acceptable salt thereof.
  • the antimetabolite of any one of embodiments 1 to 5 is an antifolate or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • the antifolate of embodiment 6 is selected from the group consisting of a compound in Table 2, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • the antifolate of embodiment 6 or 7 is Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • the antifolate of embodiment 6 or 7 is Compound C, or a pharmaceutically acceptable salt thereof.
  • the antifolate of embodiment 6 or 7 is Compound D, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of a MAT2A inhibitor, or a pharmaceutically acceptable salt thereof, and a second pharmaceutical composition comprising a therapeutically effective amount of an antimetabolite, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • the MAT2A inhibitor of embodiment 11 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor of embodiment 11 or 12 is selected from the group consisting of a compound in Table 1 , or a pharmaceutically acceptable salt thereof.
  • the antimetabolite of any one of embodiment 11 to 13 is an antifolate, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • the antifolate of embodiment 14 is selected from the group consisting of a compound in Table 2, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound C, or a pharmaceutically acceptable salt thereof.
  • a combination product comprising a first pharmaceutical composition comprising a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof; and a second pharmaceutical composition comprising a therapeutically effective amount of Compound D, or a pharmaceutically acceptable salt thereof.
  • a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with an antimetabolite.
  • the MAT2A inhibitor of embodiment 19 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor of embodiment 19 or 20 is selected from the group consisting of a compound in Table 1 , or a pharmaceutically acceptable salt thereof. 22.
  • the antimetabolite of any one of embodiments 19 to 21 is an antifolate.
  • the antifolate of embodiment 22 is selected from the group consisting of a compound in Table 2, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with an antifolate; wherein the MAT2A inhibitor is Compound A, or a pharmaceutically acceptable salt thereof; and the antifolate is Compound B, or a pharmaceutically acceptable salt and/or a hydrate thereof.
  • a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with an antifolate; wherein the MAT2A inhibitor is Compound A, or a pharmaceutically acceptable salt thereof; and the antifolate is Compound C, or a pharmaceutically acceptable salt thereof.
  • a MAT2A inhibitor for use in treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with an antifolate; wherein the MAT2A inhibitor is Compound A, or a pharmaceutically acceptable salt thereof; and the antifolate is Compound D, or a pharmaceutically acceptable salt thereof.
  • a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with an antimetabolite.
  • the MAT2A inhibitor of embodiment 27 is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • the MAT2A inhibitor of embodiment 27 or 28 is selected from the group consisting of a compound in Table 1 , or a pharmaceutically acceptable salt thereof.
  • the antimetabolite of any one of the embodiments 27 to 29 is an antifolate.
  • the antifolate of embodiment 30 is selected from the group consisting of a compound in Table 2, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with an antifolate; wherein the MAT2A inhibitor is Compound A, or a pharmaceutically acceptable salt thereof; and the antifolate is Compound B, or a pharmaceutically acceptable salt and/or hydrate thereof.
  • a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with an antifolate; wherein the MAT2A inhibitor is Compound A, or a pharmaceutically acceptable salt thereof; and the antifolate is Compound C.
  • a MAT2A inhibitor in the manufacture of a medicament for treating cancer, wherein the MAT2A inhibitor is to be administered simultaneously or sequentially with an antifolate; wherein the MAT2A inhibitor is Compound A, or a pharmaceutically acceptable salt thereof; and the antifolate is Compound D, or a pharmaceutically acceptable salt thereof.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a MAT2A inhibitor and administering to the subject a therapeutically effective amount of an antimetabolite, wherein the MAT2A inhibitor is a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein
  • X is N or C
  • R 3 is C 1-6 haloalkyl, halo, or C 3-6 cycloalkyl
  • R 2 is -NR 4 R 5 ;
  • R 4 is hydrogen or C 1-6 alkyl
  • R 5 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 1 is phenyl, wherein phenyl is substituted with 0-2 halo.
  • MAT2A inhibitor is selected from the group consisting of a compound from Table 1 , or a pharmaceutically acceptable salt thereof.
  • Compound A1 or a pharmaceutically acceptable salt thereof 13. The method of any one of embodiments 1 to 12, wherein the antimetabolite is an antifolate.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and administering to the subject a therapeutically effective amount of an antimetabolite, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of Compound A1 , or a pharmaceutically acceptable salt thereof, and administering to the subject a therapeutically effective amount of an antimetabolite, or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • the cancer is selected from the group consisting of leukemia, glioma, lung cancer, esophageal cancer, MTAP-deficient pancreatic ductal adenocarcinoma (PDAC), melanoma, pancreatic, non-small cell lung cancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, anal cancer, stomach cancer, colon cancer, colorectal cancer, soft tissue sarcoma, non-Hodgkin lymphoma, gastric cancer esophagogastric cancer, oesophageal cancer, malignant peripheral nerve sheath tumor, mesothelioma, salivary gland tumors, urothelial cancers, gastrointestinal cancer, and sarcomas.
  • PDAC pancreatic ductal adenocarcinoma
  • a method of inhibiting tumor growth or slowing the rate of tumor growth in a subject with an MTAP deleted cancer comprising: a) sequential administration of a MAT2A inhibitor and an antimetabolite, wherein i) the MAT2A inhibitor is administered prior to the antimetabolite, or ii) the antimetabolite is administered prior to the MAT2A inhibitor; or b) simultaneous administration of a MAT2A inhibitor and an antimetabolite.
  • a method of treating cancer in a subject in need thereof comprising administering to the subject a MAT2A inhibitor and an antimetabolite, wherein the subject has undergone a previous cancer treatment regimen without a MAT2A inhibitor.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • Compound A and Compound B as single-agent anti-tumor agents and in combination was assessed in the RT112/84 human bladder tumor cell line.
  • Cells were expanded in RPMI-1640 (Gibco, Catalog Number 1 1875093) with 10% fetal bovine serum. These cells were free of mycoplasma and authenticated by STR profiling.
  • RPMI-1640 Gibco, Catalog Number 1 1875093
  • fetal bovine serum 10% fetal bovine serum
  • STR profiling One to Three million cells in log growth phase were resuspended in Hanks Balanced Salt Solution containing 50% Matrigel and implanted subcutaneously into the flank of each recipient female Crl:NU-Foxn1 nu mouse.
  • mice were housed in microisolator cages with corn cob bedding with additional enrichment consisting of sterile nesting material (Innovive) and Bio-huts (Bio-Serv). Water (Innovive) and diet (Teklad Global 19% Protein Extruded Diet 2919, Irradiated) were provided ad libitum. The environment was maintained on a 12-hour light cycle at approximately 68-72 °F and 40-60% relative humidity.
  • Tumor growth inhibition (TGI) was calculated by [(TV controlfinal - TV treatedfi na i)/(TV controlfinal - TV contro nitiai) x 100].
  • TV was analyzed for statistical significance utilizing GraphPad Prism version 9.1.0. Repeated Measures 2-Way ANOVA with Tukey’s Multiple Comparisons was utilized, and P-values were presented from the final tumor measurement and were considered statistically significant if less than 0.05.
  • Compound A and Compound B were found to result in no single agent activity in RT112/84. When Compound A was combined with Compound B, the combination provided significant anti-tumor activity.
  • Mean tumor volume at dosing start was approximately 156 mm 3 , with ten mice randomized to each treatment group. Mice were dosed orally, once per day, with Vehicle, Compound A at 10 mg/kg, or dosed for 5 consecutive days followed by two days holiday by intraperitoneal (IP) injection of Compound B at 75 mg/kg, or Compound A at 10 mg/kg and Compound B at 75 mg/kg.
  • the vehicle group was a combination of Vehicle A (for Compound A, 0.5% 400 cps methylcellulose with 0.5% Tween-80 in sterile water) and Vehicle B (for Compound B, Saline).
  • Treatment with Compound A resulted in -4% TGI, while Compound B alone resulted in 14% TGI.
  • the combination of Compound A and Compound B significantly inhibited tumor growth.
  • Mean tumor volume at dosing start was approximately 250 mm 3 , with eight mice randomized to each treatment group. Mice were dosed orally, once per day, with Vehicle, Compound A at 10 mg/kg, or dosed for 5 consecutive days followed by two days holiday by intraperitoneal (IP) injection of Compound B at 75 mg/kg, or Compound A at 10 mg/kg and Compound B at 75 mg/kg.
  • the vehicle group was a combination of Vehicle A (for Compound A, 0.5% 400 cps methylcellulose with 0.5% Tween-80 in sterile water) and Vehicle B (for Compound B, Saline).
  • Treatment with Compound A resulted in 26% TGI, while Compound B alone resulted in 21% TGI.
  • the combination of Compound A and Compound B significantly inhibited tumor growth.
  • the MTAP-deleted bladder CDX model RT-112/84 was found to be resistant to either Compound A or Compound B.
  • Compound A when combined with Compound B provides significant anti-tumor activity.
  • Mean tumor volume at dosing start was approximately 213 mm3, with nine mice randomized to each treatment group. Mice were dosed orally, once per day, with Vehicle, Compound A at 3 mg/kg or 10 mg/kg, or once weekly with 50 mg/kg IP Compound C, or Compound A at 3 mg/kg or 10 mg/kg and Compound C at 50 mg/kg IP.
  • the vehicle group was a combination of Vehicle A (for Compound A, 0.5% 400 cps methylcellulose with 0.5% Tween-80 in sterile water) and Vehicle B (for Compound C, Saline).
  • Treatments as monotherapies resulted in 9% TGI for 3 mg/kg QD Compound A, 81% TGI for 3 mg/kg QD Compound A, and 11% TGI for Compound C.
  • the combination of Compound A at 3 mg/kg QD and Compound C produced 66% TGI.
  • the combination of Compound A at 10 mg/kg QD and Compound C produced 68% TGI, See Table 5 and Figure 3.
  • the combination of Compound A and Compound C produced significant tumor growth inhibition when Compound A was administered at the sub-maximally efficacious dose of 3 mg/kg QD.
  • the MTAP-deleted Gastric PDX CTG-0707 was found to be sensitive to Compound A, but not Compound C.
  • Compound A was administered at a sub-maximally efficacious dose of 3 mg/kg QD and combined with Compound C, a significant anti-tumor growth response occurred.
  • the response observed with Compound A at 3 mg/kg QD when combined with Compound C was similar to that observed for Compound A at 10 mg/kg QD as a monotherapy.
  • Compound C was not found to result in single agent activity.
  • Compound A resulted in significant efficacy at 10 mg/kg.
  • Compound A When Compound A was combined with Compound C, the combination provided significant tumor growth inhibition compared to when 3 mg/kg Compound A was combined with Compound C.
  • Compound A at 10 mg/kg QD produced the maximal tumor growth inhibition and no further combination benefit was determined.
  • the combination of Compound A and Compound C produced significant tumor growth inhibition when Compound A was administered at the sub-maximally efficacious dose of 3 mg/kg QD.
  • Mean tumor volume at dosing start was approximately 145 mm 3 , with ten mice randomized to each treatment group. Mice were dosed orally, once per day, with Vehicle, Compound A at 10 mg/kg, or dosed for 5 consecutive days followed by two days holiday by intraperitoneal (IP) injection of Compound B at 75 mg/kg, or once weekly with 50 mg/kg IP Compound C, or Compound A at 10 mg/kg and Compound B at 75 mg/kg, or Compound A at 10 mg/kg and Compound C at 50 mg/kg.
  • the vehicle group was a combination of Vehicle A (for Compound A, 0.5% 400 cps methylcellulose with 0.5% Tween-80 in sterile water) and Vehicle B (for Compound B and C, Saline).
  • Treatments as monotherapies resulted in 94% TGI for Compound A, 56% TGI for Compound B and 74% TGI for Compound C.
  • the combination of Compound A and B produced a mean TGI of 87%.
  • the combination of Compound A and Compound B increased the rate of mice with tumor regressions (a reduction in tumor volume beyond that of the tumor volume at the initiation of treatment; e.g. >100% TGI) from 20% to 30%.
  • the combination of Compound A and Compound C resulted in 98% TGI and increased the tumor regressions to 40%, See Table 6 and Error! Reference source not found..
  • the combination of Compound A and Compound B or Compound C enriched for mice with regressions and resulted in significant tumor inhibition.
  • SAM s-adenosyl methionine
  • Mean tumor volume at dosing start was approximately 477 mm 3 , with 9 mice randomized to each treatment group. Mice were dosed orally, once per day, with Vehicle, Compound A at 10 mg/kg, or dosed for 5 consecutive days by intraperitoneal (IP) injection of Compound B at 75 mg/kg, or twice with 50 mg/kg IP Compound C (day 1 and day 5), or Compound A at 10 mg/kg and Compound B at 75 mg/kg, or Compound A at 10 mg/kg and Compound C at 50 mg/kg.
  • the vehicle group was a combination of Vehicle A (for Compound A, 0.5% 400 cps methylcellulose with 0.5% Tween-80 in sterile water) and Vehicle B (for Compound B and C, Saline).
  • the MTAP-deleted NSCLC xenograft model NCI-H838 was found to be sensitive to Compound A, Compound B, and Compound C.
  • Compound A when combined with Compound B or Compound C provided an improvement for the individual response rate and additionally benefitted the response by providing early disease stabilization.
  • Administration of Compounds B and C alone caused an increase in SAM in both tumor and plasma, while a sustained decrease in plasma and tumor SAM was observed upon administration of Compound A either as a single agent or in combination with Compound B or C.
  • Example 4 In Vitro Proliferation Screen Identifies Combination Benefit with MAT2A and Pemetrexed Inhibition
  • a 10-day proliferation screen was performed in a panel of 10 MTAP-deficient pancreatic, non-small cell lung, and bladder cancer cell lines.
  • Optimal cell seeding for all cell lines was determined by assessing the growth over a range of seeding densities in a 384- well format to identify conditions that permitted proliferation for 10 days.
  • Cells were then plated at the optimal seeding density in the presence of 20-150 nM of Compound A or DMSO vehicle control. Cells were incubated at 37°C with 5% CO2 for 4 days to allow for target engagement of the pre-treatment compound. Maintaining the pre-treatment condition, cells were also treated with an 11 -point, three-fold titration series of compounds from a chemically diverse library of 424 compounds.
  • the combination compound concentrations ranged from 0.2 nM to 14,679 nM.
  • a plate of cells was harvested at the time of combination compound addition to quantify the number of cells at the start of the combination (To).
  • the harvested cells were lysed with Promega CellTiter-Glo (CTG) reagent according to the manufacturer’s protocol and the chemiluminescent signal was detected on a Synergy Neo plate reader.
  • CTG estimates cell number through detection of cellular ATP levels.
  • Cells were incubated with the drug combinations at 37°C with 5% CO2 for an additional 6 days for a total of a 10-day assay including the pre-treatment. Cells were then lysed with CTG and the chemiluminescent signal was measured.
  • Pemetrexed (Compound B) was tested in combination with Compound A in 10 MTAP-deficient cancer cell lines. In four of these cell lines, i.e., UMUC5, NCI-H2228, SW900 and NCI-H2170 cell lines, the combination showed 3.3-, 2.3-, 2.2- and 5.2-fold shifts in growth IC 50 , respectively (Table 9).
  • Pemetrexed (Compound B) in combination with Compound A was also examined in the NCI-H838 cell line where two different pre-treatment doses of Compound A were tested in separate experiments. In the first experiment, a 9.2- fold shift in the Pemetrexed growth IC 50 was observed when cells were pre-treated with 20nM Compound A. In the second experiment, a 4.7-fold shift in the Pemetrexed growth IC 50 was observed when cells were pre-treated with 150nM Compound A (Table 9).
  • Table 9 Growth IC50 values with and without Compound A pre-treatment in 10 cancer cell lines
  • Example 5 In Vitro Synergistic Growth Inhibition with MAT2A Inhibitor and Pemetrexed Combination
  • a 10-day proliferation assay was performed in a panel of MTAP-deficient pancreatic, non-small cell lung, and bladder cancer cell lines.
  • Optimal cell seeding for all cell lines was determined by assessing the growth over a range of seeding densities in a 384-well format to identify conditions that permitted proliferation for 10 days.
  • Cells were then plated at the optimal seeding density and treated with a double titration of a 16-point, two-fold dilution series of Compound A and a 16-point, two-fold dilution series of Pemetrexed (Compound B). The double titrations were compared to 16-point, two-fold dilution series of each single agent.
  • Concentrations tested for Compound A and Pemetrexed alone or in combination ranged from 0.6 nM to 19,250 nM.
  • An untreated plate of cells was harvested at the time of dosing to quantify the number of cells at the beginning of the combination (To) using CTG as described in example 1.
  • Combination plates were incubated at 37 °C in 5% CO2for a total of 10 days prior to cell lysis and CTG measurement.
  • Synergy is measured at all tested concentrations of Compound A across all concentrations of Pemetrexed using excess over Bliss analyses for the NCI-H838 (A), SW900 (B), UMUC5 (C), UMUC11 (D), HuP-T4 (E) and Pane 03.27 MTAP CRISPR Knock- out Clone 31 (F) cell lines. Scores between 1 and 10 were considered additive, scores >10 were considered synergistic. Excess over Bliss scores were only calculated for combinations exhibiting greater than 20% growth inhibition. All reported values are an average of two biological replicates.
  • Table 10A Excess over Bliss Synergy of Compound A and Pemetrexed Co-treatment Combinations in NCI-H838 cell line.
  • Table 10C Excess over Bliss Synergy of Compound A and Pemetrexed Co-treatment Combinations in UMUC5 cell line Table 10C (cont’d)
  • Table 10D Excess over Bliss Synergy of Compound A and Pemetrexed Co-treatment Combinations in UMUC11 cell line Table 10D (cont’d)
  • Table 10E Excess over Bliss Synergy of Compound A and Pemetrexed Co-treatment Combinations in HuP-T4 cell line Table 10E (cont’d)
  • Table 10F Excess over Bliss Synergy of Compound A and Pemetrexed Co-treatment Combinations in Pane 03.27 MTAP CRISPR Knock-Out Clone 31 cell line Table 10F (cont’d)
  • the anti-tumor efficacy of Compound A and Compound B as single agent and in combination was assessed in MTAP deleted NSCLC PDX mouse model - LXFA737.
  • Tumors were implanted subcutaneously (s.c.) in one flank of NMRI nu/nu mice. Animals were housed in individually ventilated cages (TECNIPLAST Sealsafe-IVC-System, TECNIPLAST, Hohenpeissenberg, Germany). They were kept under a 14L:10D artificial light cycle. The temperature inside the cages was maintained at 22 -26 °C with a relative humidity of 45-65% and 60-65 air changes/hour in the cage.
  • the animals were fed autoclaved Teklad Global Extruded 19% Protein Rodent Diet from Envigo RMS SARL and had access to sterile filtered and acidified (pH 2.5) tap water that was changed twice weekly. Feed and water were provided ad libitum. All materials were autoclaved prior to use
  • mice were housed in microisolator cages with corn cob bedding with additional enrichment consisting of sterile nesting material (Innovive) and Bio-huts (Bio-Serv). Water (Innovive) and diet (Teklad Global 19% Protein Extruded Diet 2919, Irradiated) were provided ad libitum
  • Tumor growth inhibition (TGI) was calculated by [(TV control final - TV treated final )/(TV control final - TV control initial ) x 100].
  • TV was analyzed for statistical significance utilizing GraphPad Prism version 9.1.0. Repeated Measures 2-Way ANOVA with Tukey’s Multiple Comparisons was utilized, and P-values were presented from the final tumor measurement and were considered statistically significant if less than 0.05.
  • Compound A and B The antitumor efficacy of Compound A and B was assessed in monotherapy and in combination in the lung tumor model LXFA737 implanted s.c. in NMRI nu/nu mice.
  • Compound A monotherapy slowed LXFA737 tumor growth almost to stasis with a TGI value of 91.4% ( Figure 9, Table 11).
  • the reduction in tumor volume compared to the control group was statistically significant (Kruskal-Wallis test/Dunn’s post test).
  • Compound B monotherapy slowed LXFA737 tumor growth with a TGI value of 64.8% without a statistically significant reduction in tumor volume compared to the control group ( Figure 9, Table 11).
  • Example 7 MAT2A and Pemetrexed Demonstrate Synergistic Growth Inhibition in In Vitro MTAP-Deficient Models
  • a panel of 13 MTAP-deficient non-small cell lung cancer (NSCLC), bladder, pancreatic, gastric, esophageal, and head and neck squamous cell carcinoma (HNSCC) cancer cell lines was used to assess the combinatory effect of a MAT2A inhibitor (Compound A) and pemetrexed (Compound B) using Horizon Discovery’s High Throughput Screening platform.
  • NSCLC non-small cell lung cancer
  • HNSCC head and neck squamous cell carcinoma
  • cells were seeded at 150 cells/well in a 384-well plate, and 24 hrs later, co-treated with a 5- point titration of each compound in an optimized 6x6 dose matrix for 6 days.
  • Cells were subsequently lysed with Promega CellTiter-Glo (CTG) 2.0 reagent according to the manufacturer's protocol and the chemiluminescent signal was measured using a PerkinElmer EnVision plate reader for cell number quantification.
  • CTG Promega CellTiter-Glo
  • the percent of growth inhibition is calculated as: lf T ⁇ V 0 : 100*(1-(T-V 0 )/V 0 ) lf T> V 0 : 100*(1-(T-V o )/(V-V 0 )) where T is the signal measure for a test article, V is the vehicle-treated control measure, and V 0 is the vehicle control measure at To).
  • T is the signal measure for a test article
  • V the vehicle-treated control measure
  • V 0 is the vehicle control measure at To).
  • This formula is derived from the growth inhibition calculation used in the National Cancer Institute’s NCI-60 high throughput screen.
  • the percent growth inhibition is used to generate dose-response curves and Gl 50 calculations for single drug activity and drug combination synergy in Horizon’s Chalice Analyzer software. 100% and > 100% growth inhibition represented cytostasis and cytotoxicity, respectively.
  • Synergy Score log f x log f Y Z max(0,l data )(l data - I Loewe )
  • the fractional inhibition for each component agent and combination point in the matrix is calculated relative to the median of all untreated/vehicle-treated control wells.
  • the Synergy Score equation integrates the observed growth inhibition each at point in the dose matrix in excess over predicted growth inhibition and dilution factors of individual compounds.
  • the inclusion of positive inhibition gating or an l data multiplier removes noise near the zero-effect level, and biases results for synergistic interactions at that occur at high activity levels. Combinations with higher maximum growth inhibition effects or those which are synergistic at low concentrations will have higher Synergy Scores.
  • a Synergy Score of > 3.0 was considered synergistic, given that it corresponded with high growth inhibition and > 20% excess over Loewe additivity model at multiple dose points.
  • the growth inhibition is presented as a percent of TO for each cell line in a 6x6 dose matrix. 50-100% growth inhibition is highlighted in light gray, with 100% growth inhibition representing cytostasis. Greater than 100% growth inhibition is highlighted in dark gray and represents cytotoxicity.
  • Table 12 Synergy scores for the combination of Compound A and either Compound B or D in 13 MTAP-deficient cell lines.

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Abstract

L'invention concerne une combinaison d'un inhibiteur de la méthionine adénosyltransférase II alpha (MAT2A) et d'un antimétabolite. L'invention concerne également des méthodes d'utilisation de telles combinaisons pour traiter des maladies ou des troubles, par exemple, le cancer.
PCT/US2023/015548 2022-03-18 2023-03-17 Polythérapie comprenant un inhibiteur de mat2a et un agent antimétabolite WO2023177894A1 (fr)

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