WO2020163637A1 - Bisphosphonate-linked compounds - Google Patents
Bisphosphonate-linked compounds Download PDFInfo
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- WO2020163637A1 WO2020163637A1 PCT/US2020/017071 US2020017071W WO2020163637A1 WO 2020163637 A1 WO2020163637 A1 WO 2020163637A1 US 2020017071 W US2020017071 W US 2020017071W WO 2020163637 A1 WO2020163637 A1 WO 2020163637A1
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- compound
- kbu2046
- pharmaceutically acceptable
- cells
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
- C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
Definitions
- the present invention concerns novel compounds useful in the treatment of cancer[Steve, a novel use of the compound is to treat a side-effect of the cancer - bone destruction - should this also be mentioned here?], particularly including compounds linking a bisphosphonate moiety with KBU2046, and pharmaceutically acceptable salts, co-crystals, polymorphs, solvates, hydrates, and enantiomers thereof.
- KBU2046 3-(4-fluorophenyl)chroman-4-one
- KBU2046 a first-in-class HSP90 activity modulator
- US Patent Application Publication No. 2016/0128973 Bosset et al. - Northwestern University
- KBU2046 inhibits metastasis across murine models of human prostate and breast cancer, decreases bone destruction, and prolongs survival at nanomolar concentrations after oral administration.
- metastatic cancers that locate to the bone, including metastatic cancers of the breast, prostate, lung, kidney, thyroid, bladder, esophagus, stomach, liver, pancreas, testicles, skin, head and neck, lymphomas, multiple myelomas, and sarcomas from the soft tissue or bone.
- Z is selected from the group of: rii in each instance is an integer selected from the group of 1, 2, 3, 4, 5, and 6;
- X is (-CH 2 -) n2 ;
- Ri is selected from the group of H and Ci-C 3 alkyl
- R 2 is selected from the group of H and OH; n 2 is an integer selected from the group of 0, 1, 2, and 3; n 3 is an integer selected from the group of 0 and 1; and Y is a bisphosphonate compound; or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof.
- Ri is selected from the group of methyl and ethyl.
- Ri is methyl
- Ri is ethyl
- Ri is H.
- R 2 is H.
- R 2 is OH
- ni is an integer selected from the group of 1, 2, 3, 4, and 5.
- ni is an integer selected from the group of 1, 2, 3, and 4.
- Y is selected from structures of the group below, indicated by their corresponding bisphosphonate entity:
- the waving or oscillating line passing through a solid line ( X) indicates the bond through which adjacent atoms are bound.
- FIGURE 1A graphs the effect of chemotherapy on the growth of androgen independent PC3-M PCa cells in vitro.
- FIGURE IB graphs the effect of chemotherapy on the growth of androgen independent PCa cells in vivo.
- FIGURE 2A graphs lung metastasis measured by qPCR for human Alu sequences, expressed as percent control
- FIGURE 2B represents weekly IVIS imaging of tumor.
- FIGURE 2C indicates corresponding tumor weight in tested mice.
- FIGURE 3A indicates effects on AR-responsive gene selection in LNCaP cells treated with R1881 (R), KBU2046 (46) and/or enzalutamide.
- FIGURE 3B indicates effects on AR-responsive gene selection in VCaP cells treated with R1881 (R), KBU2046 (46) and/or enzalutamide.
- FIGURE 3C depicts effects of enzalutamide on LNCaP cell growth.
- FIGURE 3D depicts effects of enzalutamide on VCaP cell growth.
- FIGURE 3E represents effects on AR activation through Western blots of nuclear (N) and cytoplasmic (C) preparations of cell extracts probed for AR, laminin B1 or a-tubulin.
- FIGURE 3F graphs the effect on tumor outgrowth after androgen deprivation therapy in LNCaP/AR-luc cells implanted subcutaneously into castrate mice, followed by KBU2046 treatment.
- FIGURE 3G graphs the effect on tumor outgrowth after androgen deprivation therapy in LNCaP/AR-luc cells implanted orthotopically into castrate mice, followed by KBU2046 treatment.
- FIGURE 4A provides Western blot representations of protein production following KBU2016 administration in RAW 267.4 cells.
- FIGURE 4B depicts effects on cell morphology when RAW 267.4 cells were treated with RANKL and with KBU2046.
- FIGURE 4C demonstrates tartrate resistant acid phosphatase expression in treated cells.
- FIGURE 4D graphs bone degradation as quantified bone surface area.
- FIGURE 5A graphs bone degradation as quantified bone surface area when RAW 267.4 cells were treated with KBU2046, zoledronic acid, or the combination.
- FIGURE 5B depicts effects on bone degradation when RAW 267.4 cells were treated with KBU2046, zoledronic acid, or the combination.
- FIGURE 5C-E graphs cell viability, cytotoxicity and apoptosis, as measured by a Triplex Assay, when RAW 267.4 cells were treated with KBU2046, zoledronic acid, or the combination.
- FIGURE 5F depicts effects on bone degradation, measured by computed tomography, after intra-cardiac injection of human PC3 prostate cancer cells when mice were treated with KBU2046, zoledronic acid, or the combination.
- FIGURES 6G and 6H represent the effect of compound G herein in inhibiting osteoclast- mediated bone degradation.
- FIGURES 61 and 6J represent the effect of compound FI herein in inhibiting osteoclast-mediated bone degradation.
- FIGURES 6K and 6L represent the effect of compound I herein in inhibiting osteoclast-mediated bone degradation.
- FIGURE 7 represents the effects of experimental compound in the inhibition of PCa cell motility.
- FIGURE 13 represents KBU2046 does not inhibit activity of adriamycin in MDA-MB-231 cells.
- FIGURE 14 represents KBU2046 does not inhibit activity of adriamycin in PC3-M cells.
- FIGURE 15 represents KBU2046 does not inhibit activity of vinblastine in MDA-MB-231 cells.
- FIGURE 16 represents KBU2046 does not inhibit activity of vinblastine in PC3-M cells.
- FIGURE 17 represents KBU2046 does not inhibit activity of taxol in MDA-MB-231 cells.
- FIGURE 18 represents KBU2046 does not inhibit activity of taxol in PC3-M cells.
- Ri, R2, , X, Y, and Z are as defined for Formula (I), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof. Also provided is a compound of Formula (lb):
- Ri, R 2 , ni, X, Y, and Z are as defined for Formula (I), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof.
- Ri, R 2 , X, Y, and Z are as defined for Formula (I), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof.
- Another embodiment provides a compound of Formula (lc), wherein Ri is selected from the group of FI and methyl; and is an integer selected from the group of 1, 2, and 3; n3 is an integer selected from the group of 1 and 2; and Z is selected from the group of: or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof.
- Ri is selected from the group of FI and methyl; and is an integer selected from the group of 1, 2, and 3; n3 is an integer selected from the group of 1 and 2; and Z is selected from the group of: or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof.
- n 3 is 0 and Ri is methyl.
- n3 is 1.
- ni is an integer selected from the group of 1, 2, 3, 4, 5, and 6;
- X is (-CH 2 -)n 2 ; n 2 is an integer selected from 0, 1, 2, and 3; and Y is a bisphosphonate compound; or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof.
- a further embodiment provides a compound of Formula (Id), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, wherein ni is an integer selected from the group of 1, 2, 3, 4, and 5; and n2, X, and Y are as defined for Formula (Id), above.
- a still further embodiment provides a compound of Formula (Id), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, wherein is an integer selected from the group of 1, 2, 3, and 4; and n2, X, and Y are as defined for Formula (Id), above.
- Z is selected from the group of: ; ni is an integer selected from the group of 1, 2, 3, 4, 5, and 6; and n3 is an integer selected from the group of 0 and 1; or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof.
- a further embodiment provides a compound of Formula (II), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, wherein is an integer selected from the group of 1, 2, 3, 4, and 5; and n 2 is an integer selected from the group of 0 and 1.
- a still further embodiment provides a compound of Formula (II), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, wherein ni is an integer selected from the group of 1, 2, 3, and 4; and n 2 is an integer selected from the group of 0 and 1. Also provided is a compound of Formula (lla), or a pharmaceutically acceptable salt thereof:
- ni is an integer selected from the group of 1, 2, 3, 4, 5, and 6.
- a further embodiment provides a compound of Formula (lla), , or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, wherein is an integer selected from the group of 1, 2, 3, 4, and 5.
- a further embodiment provides a compound of Formula (lla), , or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, wherein is an integer selected from the group of 1, 2, 3, and 4.
- ni is an integer selected from the group of 1, 2, 3, 4, 5, and 6;
- X is (-CH -)n ; and n 2 is an integer selected from 0, 1, 2, and 3.
- a further embodiment provides a compound of Formula (Id), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, wherein ni is an integer selected from the group of 1, 2, 3, 4, and 5; and n2 and X are as defined Formulas (lll)-(XI), above.
- a further embodiment provides a compound of Formula (Id), above, or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, wherein is an integer selected from the group of 1, 2, 3, and 4; and n2 and X are as defined Formulas (lll)-(XI), above.
- Formulas (I), (la), (lb), (lc), (Id), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and (XI) there is a separate embodiment in which the integer represented by is 1, 2, or 3.
- references herein to Formulas (l)-(XI) include all formulas, including Formulas (I), (la), (lb), (lc), (Id), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and (XI).
- composition comprising a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof, and a pharmaceutically acceptable carrier or excipient.
- Additional methods include those specifically to cancers of the bone that originate as, and are metastatic from, cancers of the breast, prostate, lung, kidney, thyroid, bladder, esophagus, stomach, liver, pancreas, testicles, skin, head and neck, lymphomas, multiple myelomas, and sarcomas from the soft tissue or bone.
- a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof such as, but not limited to, a hormone therapeutic agent or a chemotherapeutic agent.
- the hormone therapeutic agent can be an antiestrogen (e.g., tamoxifen, toremifene, fulvestrant, raloxifene, droloxifene, idoxifene and the like), progestogens (e.g., megestrol acetate and the like) aromatase inhibitors (e.g., anastrozole, letrozole, exemestane, vorozole, exemestane, fadrozole, aminoglutethimide, exemestane, l-methyl-l,4-androstadiene-3,17-dione and the like), anti androgens (e.g., bicalutimide, nilutamide, flutamide, cyproterone acetate, and the like), luteinizing hormone releasing hormone agonist (LHRH Agonist) (e.g., goserelin, leuprolide,
- LHRH Agonist
- chemotherapy agents such as cisplatin, carboplatin, oxaliplatin, Eloxatin, (iii) anti-metabolites, such as Methotrexate, 5-fluorouracil (e.g., capecitabine), gemcitabine (2'-deoxy-2',2'-difluorocytidine monohydrochloride (.beta.
- anti-metabolites such as Methotrexate, 5-fluorouracil (e.g., capecitabine), gemcitabine (2'-deoxy-2',2'-difluorocytidine monohydrochloride (.beta.
- anthracyclines such as daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, adriamycin, bleomycin, mitomycin-C, dactinomycin, mithramycin
- taxanes such as paclitaxel, docetaxel, Taxotere, Taxol, taxasm, 7-epipaclitaxel, t-acetyl paclitaxel, 10-desacetyl-paclitaxel, 10-desacetyl-7-epipaclitaxel, 7-xylosylpaclitaxel, 10-desacetyl-7- epipaclitaxel, 7-
- a method of treatment of osteoporosis in a subject comprising administering to a subject in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, polymorph, solvate, hydrate, or enantiomer thereof.
- the subject in need of treatment of osteoporosis is a postmenopausal woman.
- the subject in need of treatment of osteoporosis is a man with osteoporosis.
- ni is an integer selected from the group of 1, 2, 3, 4, 5, and 6. Further provided are compounds of the formula:
- Pi is an integer selected from the group of 1, 2, 3, 4, 5, and 6.
- Compounds as described herein may be prepared by methods known in the art. Specific examples of synthetic routes are presented. The method below for the preparation of 3-(4- fluorophenyl)-7-hydroxychroman-4-one (Compound A) may also be seen in U.S. 2016/0128973 Al.
- Compound A may be converted to 2-((3-(4-fluorophenyl)-4-oxochroman-7-yl)oxy)acetic acid, Compound B, by methods described in Chemical & Pharmaceutical Bulletin, 39(10), 2681-90; 1991, as follows.
- compound A may also be converted to the corresponding carbonate compound, 3-(4- fluorophenyl)-4-oxochroman-7-yl phenyl carbonate, Compound C, as follows at from 0°-RT (room temperature) for about an hour.
- Zolendronic acid can be converted to 3-(3-amino-2-hydroxypropyl)-l-(2-hydroxy-2,2- diphosphonoethyl)-lH-imidazol-3-ium, Compound D, as follows.
- Nosyl group protection was performed with PEG-1 followed by N-alkylation on 0.5 g scale and isolated 0.4 g of compound 3.
- Nosyl deprotection of compound 3 was accomplished on 0.4 g [PhSH (1 eq.) / K 2 C0 3 (2.5 eq.) / DMF / RT] scale.
- Work up followed by purification provided 0.14 g of desired compound 4.
- 0.7 g of compound 4 was isolated after two steps of PEG-1 on 2 g scale.
- Coupling of compound 4 with compound F was done on 0.25 g [F (1.1 eq.) / triphosgene (0.5 eq.) / DIPEA (2 eq.) / DCM / 0 °C / lh] scale.
- Step-1 CBZ protection (Step-1) was performed on 5 g scale with 3-(methylamino)propanol (SM 1) followed by O-alkylation (Step-2), we have isolated 4.5 g of compound 5.
- CBZ deprotection (Step-2) of compound 5 was carried out on 4.5 g [Pd-C / H2 /MeOH / RT] scale to achieve 2.6 g of compound 6.
- a coupling reaction between amine intermediate 6 with triphosgene has been attempted on 500 mg [triphosgene (0.5 eq.) /NaHCOs/CI-hCh /DMF/H2O/ 0°C to RT] scale.
- SM remains unreacted even after 12 h.
- KBU2046 does not interfere with the activity of chemotherapy
- Chemotherapy is widely used in the treatment of androgen independent PCa, both docetaxel and cabazitaxel have been shown to prolong life (Tannock et al., N EnglJ Med 351, 1502-1512 (2004); Sweeney et al., N EnglJ Med 373, 737-746 (2015); and Bono et al., Lancet 376, 1147-1154 (2010)), and both are taxanes that target microtubule function, thereby inhibiting cell growth ( Lyseng-Williamson et al., Drugs 65, 2513-2531, 2005). Combining chemotherapy with KBU2046 did not affect the ability of either docetaxel or cabazitaxel to inhibit the growth of androgen independent PC3-M cells in vitro (Fig. 1A).
- Figure 1 demonstrates KBU2046 does not inhibit chemotherapy efficacy against prostate cancer.
- Figure IB depicts the effect of chemotherapy on the growth of androgen independent PCa cells in vivo.
- Unregulated cell growth and unregulated cell movement constitute two elemental processes of cancer.
- a therapeutic strategy wherein both of these processes are targeted is rationally-based.
- the PC3-M orthotopic implantation murine model allows for the quantification of primary tumor growth, the assessment of distant metastasis to the lungs, and has previously been used to measure the effects of therapy and genetic alterations on metastasis (Xu et al., Nature
- mice received orthotopic implants of PC3-M-luc cells, were treated with 0, 10 or 20 mg/kg docetaxel, and tumor growth monitored with weekly IVIS imaging. Docetaxel significantly inhibited growth compared to controls in a dose-dependent manner. Subsequently, mice with orthotopic implants of PC3-M-luc cells were treated with docetaxel, KBU2046, docetaxel+KBU2046 or vehicle, as denoted, and effects on primary tumor growth and lung metastasis quantified (Figs. 2A, 2B, and 2C). Prior studies demonstrated that it is possible to detect as few as 10 human cells per mouse organ, i.e.
- docetaxel+KBU2046 is 42% reduction, giving an experimental/calculated ratio of 1.1, or additive-to- slightly-synergistic.
- Figure 2 demonstrates that KBU2046 plus docetaxel exhibits increased anti-metastatic efficacy.
- Cohorts of N 10 mice bearing orthotopic implants of PC3-M-luc cells were treated daily with 150 mg/kg KUB2046 (46), intraperitoneal docetaxel 7.5 mg/kg weekly (doc), the combination (doc+46), or with oral and intraperitoneal vehicle (CO).
- KBU2046 treatment began 3 days before implantation and docetaxel began 1 week after.
- A Lung metastasis measured by qPCR for human Alu sequences, expressed as percent control
- B Weekly I VIS imaging of tumor.
- C Tumor weight. *denotes P ⁇ 0.05 for differences between cohorts denoted by bars. All data are mean ⁇ SEM.
- KBU2046 does not interfere with hormone therapy
- Hormonal therapy is the mainstay of treatment for metastatic PCa ( N. C. C. Network, Prostate Cancer. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) Version 4, (2016)). It is therefore important to ensure other therapeutic modalities do not interfere with it.
- Initial hormone treatment involves decreasing testicular androgen production, and is termed androgen deprivation therapy (ADT).
- ADT androgen deprivation therapy
- Disease progression which is inevitable, is termed castrate-resistant PCa, and is commonly treated with an androgen receptor (AR) antagonist, such as enzalutamide (Beer et al., N Engl J Med 371, 424-433 (2014)).
- AR androgen receptor
- KBU2046 significantly inhibited R1881-mediated PSA gene expression, consistent with inhibition of AR function.
- AR is a client protein of HSP90
- AR function requires HSP90- mediated chaperone action, and direct inhibitors of HSP90 decrease client protein expression and inhibit AR function (24-26 Fang et al., J Biol Chem 271, 28697-28702 (1996); Saporita et al., Prostate 67, 509- 520 (2007); and Ni et al., Mol Cell Biol 30, 1243-1253 (2010)).
- KBU2046 is not a direct inhibitor of HSP90, and as such does not globally decrease client protein expression.
- FISP90 activity modulator SFIAM
- KBU2046 It is a selective FISP90 activity modulator (SFIAM), and selectively modulates client proteins that regulate cell motility.
- SFIAM selective FISP90 activity modulator
- the effect of KBU2046 on AR expression and function had not been examined.
- functional AR translocates from the cytoplasm to the nucleus, and nuclear localization therefore provides a measure of functional AR.
- R1881, KBU2046, and/or enzalutamide By treating LNCaP and VCaP cells with R1881, KBU2046, and/or enzalutamide, and measuring AR expression by Western blot in resultant nuclear and cytoplasmic cellular fractions, we demonstrated that KBU2046 did not affect AR expression or nuclear localization in response to R1881, nor its inhibition by enzalutamide (Fig. 3E).
- KBU2046 did not alter tumor growth in either model. Taken together, these findings support the notion that KBU2046 does not affect androgen signaling, nor does it inhibit the efficacy of ADT or of AR antagonist therapy.
- Figure 3 helps demonstrate that KBU2046 also does not affect androgen signaling nor therapeutic targeting.
- LNCaP or VCaP cells cultured in hormone free media were treated with R1881 (R), KBU2046 (46) and/or enzalutamide (E).
- R R1881
- KBU2046 (46) enzalutamide
- E enzalutamide
- E Effects on AR activation. Western blots of nuclear (N) and cytoplasmic (C) preparations of cell extracts were probed for AR, laminin
- PCa cells secrete interleukin (IL)-ll and parathyroid hormone-related protein (PTHrP), stimulating osteoblasts to secrete receptor activator of nuclear factor kappa-B ligand (RANKL), RANKL induces osteoclasts to degrade bone, degradation of bone matrix releases insulin growth factor (IGF) and transforming growth factor (TGF) , which act to sustain PCa cell growth.
- IGF insulin growth factor
- TGF transforming growth factor
- RAW 267.4 cells differentiate into mature osteoclasts.
- RAW 267.4 cells differentiate into mature osteoclasts.
- Upon maturation osteoclast become multinucleated, express tartrate resistant acid phosphatase (TRAP), and have the capacity to form actin rings that create an occluded cavity in which bone is degraded.
- TRIP tartrate resistant acid phosphatase
- KBU2046 inhibits phosphorylation of Rail's activation motif in RANKL treated RAW 267.4 osteoclast cells, and does so in a time-dependent manner (Fig. 4A).
- RAW 267.4 cells with KBU2046 induces several structural and functional changes. It reduces RANKL-mediated formation of multinucleated cells, and those that do form have lower numbers of nuclei (see 40x panels, Fig. 4B).
- the characteristic prominent actin ring (white arrow) surrounding the resorptive cavity (yellow arrow) is readily apparent in control cells treated with RANKL ligand, but is lacking in KBU2046-treated cells (100*, panels). Consistent with it inhibiting maturation of RAW 267.4 cells, TRAP staining is decreased in KBU2046-treated cells (Fig. 4C).
- RAW 267.4 cells exhibit a phenotype characterized by isolated cells with long thin cytoplasmic extensions (Fig. 4B).
- treatment with KBU2046 markedly reduces cellular extensions, demonstrating that its ability to induce effects on RAW 267.4 cells is not RANKL dependent.
- Figure 4 represents the KBU2046 inhibition of osteoclast function.
- Figure 4A compares effects on Rafl activation.
- RAW 267.4 cells were treated with RANKL for 4 days, treated with 10 mM KBU2046 for the indicated time periods, and Western blot for the denoted proteins performed.
- B Effects on cell morphology.
- RAW 267.4 cells were treated with RANKL and with KBU2046 for 4 days, or not, and denoted, and stained for actin (green) and DAPI (blue); white arrow denotes an actin ring, yellow arrow a resorptive cavity. Representative immunofluorescent images are depicted.
- C Tartrate resistant acid phosphatase (TRAP) expression.
- Bisphosphonates modify the bone microenvironment by chemically binding to calcium-phosphate bone mineral, are then taken up by osteoclasts after they digest the bound mineral and once inside the cell, they inhibit osteoclast-mediated bone degradation (Polascik et al., Ther Clin Risk Manag 4, 261-268 (2008)).
- ZA bisphosphonate, zoledronic acid
- ZA is used clinically to decrease bone fractures in men with metastatic PCa (Saad et al., J Natl Cancer Inst 94, 1458-1468 (2002); Saad et al., J Natl Cancer Inst 96, 879-882 (2004); and James et al., JAMA Oncol 2, 493-499 (2016) ).
- ZA is administered to humans by injection, whereupon it binds to bone mineral, while the remainder is rapidly cleared from the body, and that bound to bone mineral is responsible for inhibition of osteoclast activity and resultant decrease in bone fractures in men with metastatic PCa (N. Pharmaceuticals, Zoledronic Acid package insert FDA approved drug package insert, (2007)).
- Figure 5 represents the improved efficacy seen with KBU2046 combined with ZA.
- bone degradation was tested using osteo assays performed as in Figure 4D.
- Cells were treated with KBU2046 (46), ZA at 2, 10 or 20 mM, with the indicated combinations, or vehicle (control; CO).
- Figure 5B provides representative photomicrographs of osteo assay wells. Black color denotes presence of bone matrix; RL: RANKL.
- C-E Cell viability, cytotoxicity and apoptosis.
- Treatment was oral 150 mg KBU2046/kg daily (starting 3 days before 1C injection), intraperitoneal ZA 100 pg/kg weekly (starting 1 week before 1C injection), with oral and intraperitoneal vehicle controls given as indicated.
- F Representative computed tomography images. Image types are: side view and coronal sections of skull, and axil and sagittal sections of the femurs. Red arrows denote areas of bone destruction.
- C and D Quantification of bone lesions. The macroscopic lesions in the jaw were quantified by direct measurement from CT images, and expressed as the mean ⁇ SEM percent of control. Bone density of femurs was measured from CT images, and expressed as the mean ⁇ SEM percent of control. *denotes P ⁇ 0.05 compared to control, and for groups indicated by bars.
- Findings in control cells are consistent with this process, demonstrating successive decreases in cell viability, accompanied by increases in cellular cytotoxicity and apoptosis with time.
- Findings with KBU2046 are consistent with it delaying the maturation process, and include significant increases in cell viability and decreases in cytotoxicity at 72 hours, compared to control (P ⁇ 0.05).
- the combination of ZA+KBU2046 significantly increased apoptosis and cytotoxicity at 48 hours, but there was little-to-no effect on viability at 72 hours.
- mice develop widespread metastasis to the bone, with those to the mandible being the most prominent and symptomatic.
- Mice were treated with either ZA, KBU2046, ZA+KBU2046 or vehicle (control), and at the end of the experiment CT images of the bones were obtained and metastasis to the mandible and femur quantified (Figs. 5F-H).
- ZA did not impair KBU2046 efficacy.
- bone density was significantly (P ⁇ 0.05) improved as compared to control by 56 ⁇ 2.7% and 22 ⁇ 2.4% with ZA or KBU2046 treatment, respectively.
- the combination of ZA+KBU2046 resulted in significant (P ⁇ 0.05) additive efficacy compared to either standalone treatment, significantly increasing density by 76 ⁇ 3.7% as compared to the control treatment cohort.
- metastasis is responsible for over 90% of mortality (40), and for PCa it is responsible for essentially 100% (41, 42 Norgaard et al J Urol 184, 162-167 (2010); and Pound et al JAMA 281, 1591-1597 (1999)).
- KBU2046 and its ability to serve as a SHAM agent, selectively inhibiting Rafl activation, precision targeting of cell motility and resultant metastasis is now possible.
- Increased cancer cell motility is a characteristic of cancer which represents a clinically relevant driver of morbidity and mortality, and constitutes an important therapeutic target that we can now access. As such, we believe it is centrally important to consider it as one of several abnormal functions.
- anti-motility therapy can be deployed in a combined non-interfering manner with multiple classes of agents previously established to have efficacy in humans. Specifically, we demonstrate sustained efficacy in conjunction with several differentially acting cytotoxic chemotherapeutic agents, and do so in cell culture based studies as well as in two murine models, one utilizing subcutaneous and one utilizing orthotopic implantation. In the case of ZA, an agent that modifies the bone microenvironment, we also demonstrate that anti-motility therapy does not interfere with its activity. If fact we demonstrate that it enhances it. Here too, experiments spanned cell culture based and human murine xenograft based models of bone destruction.
- Docetaxel + KBU2046 not only retained the growth inhibitory efficacy of docetaxel but also exhibited additive efficacy at inhibiting metastasis.
- Docetaxel is a cytotoxic chemotherapeutic agent that inhibits cell growth and induces cell death through apoptosis, and is widely used across several cancer types inclusive of PCa. Such a strategic approach would be applicable to existing clinical scenarios where docetaxel is used to treat PCa, especially in the newly diagnosed metastatic setting, where the combination would serve to decrease formation of secondary metastasis. Because robust pre-clinical systemic models of the formation of metastasis as a function of targeting the androgen axis are lacking, we have not demonstrated that KBU2046 would provide additive
- KBU2046 will inhibit the motility of androgen- responsive PCa cell lines (Xu et al, above). Further, KBU2046 did not interfere with AR antagonist therapy mediated by enzalutamide, a widely used agent shown to decrease metastasis in humans (Hussain et al., N EnglJ Med 378, 2465-2474 (2016)).
- a multi-functional therapy approach may provide a platform to scale back ZA dosing, minimizing the potential for osteonecrosis while retaining protection against bone related events.
- the effects upon tumor growth and formation of metastasis were measured in athymic mice given orthotopic implants of PC3-M cells, and measuring primary tumor growth and quantifying metastasis to the lungs.
- the effects of hormone therapy on cell growth and PSA expression were measured on LNCaP or VCaP cells grown in vitro, while effects on tumor growth evaluated LNCaP-AR cells implanted either subcutaneously or orthotopically.
- the ability of KBU2046 and ZA to inhibit bone destruction was measured by adding osteoclasts to Osteo-Assay plates, and measuring pit formation. Inhibition of bone destruction in athymic mice was measured by CT scan of animals after intracardiac injection of PC3 cells. Inhibition of Rafl phosphorylation in osteoclasts was measured by Western blot, while changes in the actin cytoskeleton and cell morphology were measured by immunofluorescent microscopy.
- the following prostate cancer cells lines, PC-3, LNCaP, and VCaP were obtained from American Type Culture Collection, the constitutively active luciferase expressing PC3-Luc cell line was obtained from PerkinElmer, the origin a characteristics of PC3-M cells have been previously described by us (Liu et al., Prostate cancer and prostatic diseases 4, 81-91 (2001)).
- the constitutively active luciferase expressing PC3-M-luc cell line was established by transducing the parental cell line with pGL4.50 luciferase reporter (Promega), and culturing under hygromycin selection for stable integration.
- the LNCaP/AR-luc cell line was kindly provided by Charles Sawyers (Tran et al, Science 324, 787-790 (2009)).
- the osteoclasts precursor mouse macrophage cell line Raw 264.7 was obtained from American Type Culture Collection. All cells were cultured as previously described ( Xu et al. above; Liu et al., Prostate cancer and prostatic diseases 4, 81-91 (2001); and Korenchuk et al., In Vivo 15, 163- 168 (2001), were maintained at 37°C in a humidified atmosphere of 5% carbon dioxide with biweekly media changes. All cell lines were drawn from stored stock cells, and replenished on a standardized periodic basis and were routinely monitored for Mycoplasma (PlasmoTestTM, InvivoGen, San Diego, CA).
- Cells were authenticated by the following: they were acquired from the originator of that line, grown under quarantine conditions, expanded and stored as primary stocks and not used until following conditions were met: mycoplasma negative; through morphologic examination; growth characteristics; hormone responsiveness or lack thereof.
- KBU2046 was synthesized as previously described (5).
- Enzalutamide (#S1250), docetaxel (#S1148) and zoledronic acid (#S1314) were purchased from
- Enzalutamide mediated growth inhibition was assessed using Sulforhodamine B (SRB) growth inhibition assays, were performed as previously described (49).
- SRB Sulforhodamine B
- LNCaP and VCaP cells were pre-incubated in the charcoal-striped medium containing 10 pM KBU2046 or vehicle control for 72 hours. Cells were then stimulated with 1.0 nM R1881 and treated for 24-hours with 10 pM KBU2046 or vehicle control in the presence or absence of 10 pM enzalutamide.
- the nuclear and cytosolic subcellular fractions of the cells were prepared using the NE-PER Nuclear and Cytoplasmic Extraction Kit (Pierce, Waltham, MA) according to the manufacturer's instructions. Protein was quantified by BCA assay (Thermo-Fisher Scientific, Waltham, MA), per manufacturer's instructions.
- Pierce ECL western blotting substrate (#32106) and SuperSignal West Femto maximum sensitivity substrate (#34096) were purchased from Thermo Scientific. All primary antibodies were used at a dilution of 1:1000 and corresponding secondary antibodies used at a dilution of 1:5000.
- DylightTM Phallodin (#12935) was purchased from Cell Signaling Technology.
- Raw 264.7 cells were grown in differentiation medium (described below), with or without KBU2046, for 4 days on a Chamber Slide (Nunc Lab-Tek). Chambers were washed once with PBS, followed by 10-minute fixation in cold 10% neutral-buffered formalin (VWR) and a post-fixation wash with PBS. Permeabilization was achieved with incubation in 0.1% Triton X-100 (Sigma) for 5 minutes, and then blocked overnight at 4°C with 1% BSA (Sigma) containing 10% goat serum (Thermo Fisher
- RAW 264.7 cells were suspended in osteoclasts differentiation media (MEM- alpha (Gibco) with 10% FBS, 1% antibiotic-antimycotic and 50 ng/ml RANKL (EMD Millipore, R0525- 10UG)) and plated in 96 well Osteo Surface Assay plates (Corning) at 5000 cells per well.
- MEM- alpha Gibco
- FBS fetal bovine serum
- RANKL EMD Millipore, R0525- 10UG
- Osteo Surface Assay plates Corning
- the osteosurface was pre-coated for 30 minutes at 25°C with a 0, 2, 10, or 20 mM solution of ZA suspended in sterile water, followed by a gentle rinsing in PBS to remove free compound prior to plating of cells.
- the ApoTox-Glo triplex assay (Promega) was performed to assess cell viability, cytotoxicity and caspase-3/7 activation, per manufacturer's instructions.
- 5000 Raw 264.7 cells were plated in 96- well assay plates and cultured in the osteoclasts differentiation media for four days at which point the media was replenished with or without KBU2046 and cell responses measured after 24, 48, and 72 hrs following the manufactures protocol.
- PCa subcutaneous implantation 2.5 x 10 5 PC3-M cells in sterile PBS were implanted into the right flank of 6-7 week old male athymic nude mice (Charles River) and tumor growth measurements were performed twice a week as previously described by us ( Gordon et al., Chemotherapy-induced monoamine oxidase expression in prostate carcinoma functions as a cytoprotective resistance enzyme and associates with clinical outcomes. PLoS One 9, el04271 (2014)).
- Experimental groups were randomly assigned to cages prior to the initiation of the study. Tumor measurements were obtained in a blinded fashion, and tumor volumes were calculated with the following formula: length x (width) 2 x 0.5.
- PCa orthotopic implantation Orthotopic implantation of 2.5 x 10 5 PC3M-luc into 7-8 week old male athymic mice was performed as previously described by us (5, 52 Xu et al., above; and Pavese et al., J Vis Exp, e50873 (2013)).
- Daily oral gavage treatment with 150mg/kg KBU2046 or was initiated 3 days prior to implantation and continued throughout the duration of the study.
- Weekly IP injections with 7.5 mg/kg docetaxel or control were administered beginning one week post implantation.
- Primary tumor out growth was monitored via weekly IVIS imaging. At the completion of the study the primary tumor was resected and weighed and lungs were resected and snap frozen.
- the snap frozen tissue was pulverized, DNA isolated and Alu- sequencing performed as previously described (19).
- the following custom TaqMan primer probe set was utilized: forward primer (101 F) GGTGAAACCCCGTCTCTACT, reverse primer (206 R) GGTTCAAGCGATTCT CCTGC, and hydrolysis probe (144RH) CGCCCGGCTAATTTTTGTAT.
- the 144RH probe was labeled with a 5' fluorescent reporter (6-FAM) and a 3' fluorescent quencher (Black Hole Quencher).
- the relative content of human DNA was calculated with using the comparative C T method, C T (sample) - C T (negative control). All samples were run in triplicate and were repeated.
- Castration resistant PCa subcutaneous implantation 6-7 week old male athymic mice received trans-scrotal bilateral orchiectomy with a single incision in the midline of scrotums under general anesthesia and then allowed to recover for 10 days. Following the recovery period mice received a subcutaneous implantation of 2.0 x 10 s LNCaP/AR-luc into the right flank as previously described by us (Gordon et al., PLoS One 9, el04271 (2014)). Treatment with 80mg/kg KBU2046 or control was administered via oral gavage 5 times weekly starting 4 weeks post-implantation, prior to the emergence of the castration resistant phenotype, and continued for 12 weeks. Experimental groups were randomized prior to the initiation of treatment. Twice weekly tumor measurements were performed and androgen receptor activity monitored biweekly through IVIS imaging.
- Castration resistant PCa orthotopic implantation Castrations of athymic mice were performed as described above, and following a two-week recovery period orthotopic implantations of 5.0 x 10 5 LNCaP/AR-luc were performed as previously described by us (Xu et al., above; and, Pavese et al., above). Biweekly IVIS imaging was performed to assess androgen receptor activity and treatment with 80mg/kg KBU2046 or control via oral gavage 5 times weekly began 12 weeks post-implantation, as the castration resistant phenotype began to emerge, and continued for duration of 4 weeks. Experimental groups were randomly assigned to cages prior to the initiation of the study.
- PCa intracardiac (1C) injection 1C injection of 4.0 x 10 5 PC3-luc cells into the left ventricle of 7-8 week old athymic mice under ultrasound guidance was performed as previously described by us (Xu et al., above). Weekly IP injections of 100 pg/kg ZA or vehicle control (PBS) began 7 days prior to the 1C injection and continued throughout the duration of the study, whereas daily oral gavage treatment with 150mg/kg KBU2046 or control began 3 days prior to the 1C injection. All treatments were randomly assigned to cages prior to the initiation of the study. IVIS imaging was performed 30 min post 1C injection to confirm systemic distribution of cells and conducted weekly starting 7 days post injection, continuing for a period of 4 weeks.
- Computed Tomograpgy (CT) radiographic imaging of the entire cohort was performed with an Inveon X-ray pCT scanner (Inveon, Siemens) at the completion of the study.
- Bone disruption of the mandible was assessed in a blinded fashion utilizing the MPR of the mandible.
- the loss of bone in the periodontal cavity was calculated by measuring the distance between the edge of molar root and the wall of periodontal cavity at both coronal and transverse planes.
- Figures 6A through 6L Experimental compounds inhibit osteoclast mediated bone degradation.
- RAW 267.4 cells were plated onto Osteo Assay plates, in differentiation medium containing RANKL and the experimental compounds (or vehicle control) at the concentration indicated on day 0, medium was replenished with RANKL and treatments on day 3 day of the assay.
- Figures 8A and 8B Experimental compounds inhibit movement of human prostate cancer cells.
- I VIS imaging was performed weekly, and at the end of the experiment, computed tomography (CT) scans performed and the degree of bone destruction in the jaw quantified.
- * denotes P ⁇ / 0.05 by 2-sided Student's t test for comparisons between cohorts indicated by bars.
- KBU2046 does not inhibit the efficacy of chemotherapy
- the compounds of the disclosure may possess an asymmetric center, and can be produced as a racemic mixture or as individual enantiomers.
- the individual enantiomers may be obtained by asymmetric synthesis or by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis.
- the individual enantiomers may also be obtained by resolution of the compound by conventional means, such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high pressure liquid chromatography (HPLC) column.
- HPLC high pressure liquid chromatography
- the term “comprising” may include the embodiments “consisting of” and “consisting essentially of.”
- the terms “comprise(s),” “include(s),” “having,” “has,”“can,” “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.
- compositions or processes as “consisting of and “consisting essentially of the enumerated ingredients/steps, which allows the presence of only the named ingredients/steps, along with any impurities that might result therefrom, and excludes other ingredients/steps.
- therapeutically effective amount refers to an amount that is sufficient to effect treatment, as defined below, when administered to a subject (e.g., a mammal, such as a human) in need of such treatment.
- the therapeutically or pharmaceutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
- a "therapeutically effective amount” or a “pharmaceutically effective amount” of a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof is an amount sufficient to modulate a physiological expression or activity, and thereby treat a subject (e.g., a human) suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication.
- a therapeutically or pharmaceutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to inhibition of activity.
- the pharmaceutically effective dose per administration may be from about 1 mg to about 200 mg.
- the pharmaceutically effective dose may be from about 5 mg to about 150 mg per dose.
- the pharmaceutically effective dose may be from about 5 mg to about 100 mg per dose.
- the pharmaceutically effective dose may be from about 1 mg to about 50 mg.
- a medical professional may provide the dosage in a once- weekly regimen or divide the dosage into equal daily doses.
- a single or divided dose may be administered every 1, 2, 3, 4, 5, or 6 months.
- Treatment is an approach for obtaining beneficial or desired results including clinical results.
- beneficial or desired clinical results may include one or more of the following: (i) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); (ii) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition);
- inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
- slowing or arresting the development of one or more clinical symptoms associated with the disease or condition e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e
- inhibiting indicates a decrease, such as a significant decrease, in the baseline activity of a biological activity or process.
- “Inhibition of a given activity” refers to a decrease in the activity as a direct or indirect response to the presence of a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, relative to the activity of the condition in the absence of such compound or a pharmaceutically acceptable salt or co-crystal thereof.
- the decrease in activity may be due to the direct interaction of the compound with a biological target, or due to the interaction of the compound(s) described herein with one or more other factors that in turn affect the specific activity.
- the presence of the compound(s) may decrease an activity by directly binding to the target, by causing (directly or indirectly) another factor to decrease the activity, or by (directly or indirectly) decreasing the amount of a factor present in the cell or organism.
- the inhibition of the specified activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.
- the term "inhibitor" is understood to refer to a compound or agent that, upon administration to a human in need thereof at a pharmaceutically or therapeutically effective dose, provides the inhibition activity desired.
- Delaying the development of a disease or condition means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or condition. This delay can be of varying lengths of time, depending on the history of the disease or condition, and/or subject being treated.
- a method that "delays" development of a disease or condition is a method that reduces probability of disease or condition development in a given time frame and/or reduces the extent of the disease or condition in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a statistically significant number of subjects.
- Disease or condition development can be detectable using standard methods, such as routine physical exams, mammography, imaging, or biopsy. Development may also refer to disease or condition progression that may be initially undetectable and includes occurrence, recurrence, and onset.
- significant is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
- “Pharmaceutically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid.
- Examples of salts may include hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate (mesylate), benzenesuflonate (besylate), p-toluenesulfonate (tosylate), 2- hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate (such as acetate, HOOC-(CH 2 ) n -- COOH where n is 0-4).
- the free base can be obtained by basifying a solution of the acid salt.
- an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
- Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts.
- crystal forms and related terms herein refer to the various crystalline modifications of a given substance, including, but not limited to, polymorphs, solvates, hydrates, co-crystals, and other molecular complexes, as well as salts, solvates of salts, hydrates of salts, other molecular complexes of salts, and polymorphs thereof. Crystal forms of a substance can be obtained by a number of methods, as known in the art.
- Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, recrystallization in confined spaces such as, e.g., in nanopores or capillaries, recrystallization on surfaces or templates, such as, e.g., on polymers, recrystallization in the presence of additives, such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
- additives such as, e.g., co-crystal counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, grinding and solvent-drop grinding.
- co-crystal or "co-crystal salt” as used herein means a crystalline material composed of two or more unique solids at room temperature, each of which has distinctive physical characteristics such as structure, melting point, and heats of fusion, hygroscopicity, solubility, and stability.
- a co-crystal or a co-crystal salt can be produced according to a per se known co-crystallization method.
- co-crystal (or cocrystal) or co-crystal salt also refer to a multicomponent system in which there exists a host API (active pharmaceutical ingredient) molecule or molecules, such as a compound of Formula I, and a guest (or co-former) molecule or molecules.
- the pharmaceutically acceptable co-crystal of the compound of Formula I or of the compound of Formula II with a co-former molecule is in a crystalline form selected from a malonic acid co-crystal, a succinic acid co-crystal, a decanoic acid co-crystal, a salicylic acid co-crystal, a vanillic acid co-crystal, a maltol co-crystal, or a glycolic acid co-crystal.
- Co-crystals may have improved properties as compared to the parent form (i.e., the free molecule, zwitter ion, etc.) or a salt of the parent compound.
- Improved properties can include increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, a crystalline form of a normally amorphous compound, a crystalline form of a difficult to salt or unsalable compound, decreased form diversity, more desired morphology, and the like.
- subject and/or “patient” refers to an animal, such as a mammal, that has been or will be the object of treatment, observation, or experiment.
- the methods described herein may be useful in both human therapy and veterinary applications.
- the subject is a mammal; in some embodiments the subject is human; and in some embodiments the subject is chosen from cats and dogs.
- Subject in need thereof or “human in need thereof” refers to a subject, such as a human, who may have or is suspected to have diseases or conditions that would benefit from certain treatment; for example treatment with a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, as described herein. This includes a subject who may be determined to be at risk of or susceptible to such diseases or conditions, such that treatment would prevent the disease or condition from developing.
- pharmaceutically acceptable excipient is a pharmaceutically acceptable vehicle that includes, without limitation, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- pharmaceutically acceptable vehicle includes, without limitation, any and all carriers, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
- the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
- carrier refers to an excipient or vehicle that includes without limitation diluents, disintegrants, precipitation inhibitors, surfactants, glidants, binders, lubricants, and the like with which the compound is administered. Carriers are generally described herein and also in “Remington's Pharmaceutical Sciences” by E. W. Martin.
- Examples of carriers include, but are not limited to, aluminum monostearate, aluminum stearate, carboxymethylcellulose, carboxymethylcellulose sodium, crospovidone, glyceryl isostearate, glyceryl monostearate, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyoctacosanyl hydroxystearate, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, povidone, silicon dioxide, colloidal silicon dioxide, silicone, silicone adhesive 4102, and silicone emulsion. It should be understood, however, that the carriers selected for the pharmaceutical compositions, and the amounts of such carriers in the composition, may vary depending on the method of
- diluent generally refers to a substance that is used to dilute the compound of interest prior to delivery. Diluents can also serve to stabilize compounds. Examples of diluents may include starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, microcrystalline cellulose, and tribasic calcium phosphate.
- disintegrant generally refers to a substance which, upon addition to a solid preparation, facilitates its break-up or disintegration after administration and permits the release of an active ingredient as efficiently as possible to allow for its rapid dissolution.
- disintegrants may include maize starch, sodium starch glycolate, croscarmellose sodium, crospovidone,
- microcrystalline cellulose modified corn starch, sodium carboxymethyl starch, povidone, pregelatinized starch, and alginic acid.
- precipitation inhibitors generally refers to a substance that prevents or inhibits precipitation of the active agent from a supersaturated solution.
- a precipitation inhibitor includes hydroxypropylmethylcellulose (HPMC).
- surfactants generally refers to a substance that lowers the surface tension between a liquid and a solid that could improve the wetting of the active agent or improve the solubility of the active agent. Examples of surfactants include poloxamer and sodium lauryl sulfate.
- glidant generally refers to substances used in tablet and capsule formulations to improve flow-properties during tablet compression and to produce an anti-caking effect.
- examples of glidants may include colloidal silicon dioxide, talc, fumed silica, starch, starch derivatives, and bentonite.
- binder generally refers to any pharmaceutically acceptable film which can be used to bind together the active and inert components of the carrier together to maintain cohesive and discrete portions.
- binders may include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, copovidone, and ethyl cellulose.
- lubricant generally refers to a substance that is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process.
- a lubricant can aid the ejection of the tablet form the dies, and can improve powder flow.
- examples of lubricants may include magnesium stearate, stearic acid, silica, fats, calcium stearate, polyethylene glycol, sodium stearyl fumarate, or talc; and solubilizers such as fatty acids including lauric acid, oleic acid, and Cs/Cio fatty acid.
- compositions that contain, as the active ingredient, one or more of the compounds described, or a pharmaceutically acceptable salt, pharmaceutically acceptable co-crystal or
- compositions may be administered alone or in combination with other therapeutic agents.
- pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes, Eds.).
- compositions may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
- agents having similar utilities for example as described in those patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer.
- One mode for administration is parenteral, particularly by injection.
- the forms in which the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, may be
- incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.
- Aqueous solutions in saline may also conventionally be used for injection.
- Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
- the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- Sterile injectable solutions are prepared by incorporating a compound according to the present disclosure in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
- the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- sterile injectable solutions are prepared containing a therapeutically effective amount, e.g., 0.1 to 1000 mg, of the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof.
- the effective amount will be from about 0.1 mg to about 100 mg per dose.
- the dosage will be from about 5 mg to about 75 mg per dose. It will be understood, however, that the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.
- Oral administration is another route for administration of the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof. Administration may be via capsule or enteric coated tablets, or the like.
- the active ingredient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container.
- the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material (as above), which acts as a vehicle, carrier or medium for the active ingredient.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
- excipients in an oral formulation include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose.
- the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
- compositions as described herein can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
- Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770;
- transdermal delivery devices patches
- Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present disclosure in controlled amounts.
- the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139.
- patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- each dosage unit contains from 0.1 mg to 1 g, 0.1 mg to 700 mg, or 0.1 mg to 100 mg of a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof.
- the amount of the compound actually administered usually will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.
- the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof.
- a pharmaceutical excipient for preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof.
- these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
- the tablets or pills as described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
- compositions for inhalation or insufflation may include solutions and suspensions in
- compositions comprising the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, may contain suitable pharmaceutically acceptable excipients as described supra.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.
- the compounds, pharmaceutical compositions, and methods of treatment herein may be used in combination with other forms of cancer treatment, including chemotherapy, other bone directed therapy, inclusive of bisphosphonates or denosumab, hormone therapy, radiation therapy, surgery, small molecule therapeutics (imatinib, cisplatin, doxorubicin, Ifosfamide, methotrexate, vincristine, cyclophosphamide, etoposide, dactinomycin, eribulin mesylate, larotrectinib, pazopanib, trabectedin), including inhibitors of protein kinases, interferon, mTOR inhibitors (rapamycin, temsirolimus, everolimus, ridaforolimus), PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, AZD2281), biologies, including antibodies (trastuzumab, den
- the compounds herein may be administered in combination treatments utilizing chemotherapeutic agents such as taxol, vinblastine, vincristine, Ifosfamide (IFEX ® ), doxorubicin (ADRIAMYCIN ® ), etoposide, methotrexate, cisplatin, dactinomycin, denosumab, and cyclophosphamide (CYTOXAN ® ), or combinations thereof.
- chemotherapeutic agents such as taxol, vinblastine, vincristine, Ifosfamide (IFEX ® ), doxorubicin (ADRIAMYCIN ® ), etoposide, methotrexate, cisplatin, dactinomycin, denosumab, and cyclophosphamide (CYTOXAN ® ), or combinations thereof.
- the compounds herein may be utilized in combination therapies with additional agents, such as alendronate (FOSOMAX ® ), risedronate
- compositions comprising the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, can be prepared and placed in an appropriate container, and labeled for treatment of an indicated condition.
- an article of manufacture such as a container comprising a unit dosage form of the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, and a label containing instructions for use of the compounds.
- the article of manufacture is a container comprising a unit dosage form of the compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof, and at least one pharmaceutically acceptable vehicle.
- the article of manufacture may be a bottle, vial, ampoule, single-use disposable applicator, or the like, containing the pharmaceutical composition provided in the present disclosure.
- the container may be formed from a variety of materials, such as glass or plastic and in one aspect also contains a label on, or associated with, the container which indicates directions for use in the treatment of cancer of the bone.
- the active ingredient may be packaged in any material capable of improving chemical and physical stability, such as an aluminum foil bag.
- diseases or conditions indicated on the label can include, for example, treatment of cancer of the bone which is original in origin to bone.
- the label may be directed to treatment of a cancer that has metastasized to the bone.
- Any pharmaceutical composition provided in the present disclosure may be used in the articles of manufacture, the same as if each and every composition were specifically and individually listed for use in an article of manufacture.
- kits that includes a compound of Formula I, or a pharmaceutically acceptable salt, pharmaceutically acceptable co-crystal, pharmaceutically acceptable ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
- kit that includes a compound of Formula II, or a pharmaceutically acceptable salt, pharmaceutically acceptable co-crystal, pharmaceutically acceptable ester, stereoisomer, mixture of stereoisomers or tautomer thereof.
- the kit comprises a compound of Formula I, or a pharmaceutically acceptable salt or co-crystal thereof.
- the kit comprises a compound of Formula II, or a pharmaceutically acceptable salt or co-crystal thereof.
- the kit may comprise a label and/or instructions for use of the compound in the treatment of a disease or condition in a subject (e.g., human) in need thereof.
- the disease or condition may be associated with or mediated by the intended activity.
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Abstract
Description
Claims
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