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CN118252835A - Application of CDK inhibitor - Google Patents

Application of CDK inhibitor Download PDF

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Publication number
CN118252835A
CN118252835A CN202311791586.3A CN202311791586A CN118252835A CN 118252835 A CN118252835 A CN 118252835A CN 202311791586 A CN202311791586 A CN 202311791586A CN 118252835 A CN118252835 A CN 118252835A
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CN
China
Prior art keywords
tumor
compound
breast cancer
resistant
bai
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Pending
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CN202311791586.3A
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Chinese (zh)
Inventor
张晓琳
淡墨
张汉承
杨华
蔡聪聪
刘咏梅
赵方亮
王敏
耿佳
王以美
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Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Original Assignee
Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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Application filed by Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd, CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd filed Critical Shijiazhuang Pharmaceutical Group Ouyi Pharma Co Ltd
Publication of CN118252835A publication Critical patent/CN118252835A/en
Pending legal-status Critical Current

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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The application provides an application of a CDK inhibitor compound A in preparing an anti-tumor medicament, in particular to an application in preparing a medicament for treating CDK4/6 inhibitor resistant tumors, and provides a corresponding treatment method, wherein the structure of the compound A is shown as the following formula (I). The test result shows that the compound A has good anti-tumor activity in various human tumor cells and mice in-vivo transplantation tumor models of breast cancer piperaquine Bai Xili drug-resistant strains (including primary drug resistance and acquired drug resistance), breast cancer piperaquine Bai Xili sensitive strains, liver cancer, melanoma, acute myeloid leukemia and the like.

Description

Application of CDK inhibitor
RELATED APPLICATIONS
The present application claims priority from chinese patent application 202211681854.1 filed at month 26 of 2022, 12, the entire contents of which are incorporated herein by reference for all purposes.
Technical Field
The application belongs to the field of medicines, and particularly relates to an anti-tumor application of a CDK inhibitor.
Background
Cyclin-dependent kinases (Cyclin-DEPENDENT KINASES, CDKs) belong to the serine/threonine protein kinase family, and 20 members are currently found in total, of which 12 subtypes of CDKs 1 to 6, 11, 14 to 18, etc. are involved in cell cycle regulation, and 8 subtypes of CDKs 7 to 10, 12, 13, 19, 20, etc. are involved in transcriptional regulation. Abnormal regulation of CDKs and cyclin (Cyclins) often results in abnormal proliferation of cells and tumorigenesis.
In the cell cycle, both Cyclin D-CDK4/6 and Cyclin E-CDK2 drive G1/S phase transitions in concert, whereas Cyclin A-CDK2 is critical for S/G2 phase transitions. CDKs bind to the corresponding Cyclins to form heterodimeric complexes, which regulate the cell cycle. Early G1, growth factors, mitotic signals and the like cause the release of Cyclin D, and the combination of the growth factors and the mitotic signals with CDK4/6 to form a Cyclin D-CDK4/6 complex, trigger the phosphorylation of the allele of the substrate retinoblastoma (Rb) protein Ser807/811, dissociate transcription factor E2F, and up regulate the transcription of E2F response genes (including Cyclin A, cyclin E and the like). Late in G1, CDK2 is activated upon binding to Cyclin E, completing further phosphorylation of pRb protein (T821), driving cells through the G1/S checkpoint into S phase. In S phase CDK2 binds to Cyclin a, phosphorylates E2F, driving the cell from S phase to G2 phase.
In normal cells, cyclin D-CDK4/6 is tightly regulated by extracellular mitotic signals; in certain tumor cells, the pathway is in an overactive state, resulting in uncontrolled proliferation of tumor cells. The present clinical application of a plurality of CDK4/6 inhibitors fully verifies the effectiveness of the target, such as the pimento Bai Xili (Palbociclib) of the pyroxene, the abbe welril (Abemaciclib) of the gift, the rebaudimide (Ribociclib) of the North, and the darcinolone (Dalpiciclib) of the Henry medicine, which are all used for treating advanced or metastatic breast cancer with positive hormone receptor (HR+), negative human epidermal growth factor receptor 2 (HER 2-).
For hr+/HER 2-advanced or metastatic breast cancer patients, early treatment is often selected from endocrine therapies, commonly used endocrine therapeutic agents such as anastrozole, letrozole, exemestane, tamoxifen, toremifene, fulvestrant, megestrol, fluoxymesterone, ethinyl estradiol, and the like; early medium and high risk patients may receive chemotherapy simultaneously. For patients with advanced or metastatic disease, the current first line standard therapy is a combination of CDK4/6 inhibitors and endocrine therapy. The medical guidelines for breast cancer diagnosis and treatment (2022 edition), CSCO breast cancer diagnosis and treatment (2022 edition), NCCN breast cancer clinical practice (2022 edition) and other domestic and foreign authoritative guidelines issued by China national health and wellness Committee all raise the evidence level of CDK4/6 inhibitor combined endocrine treatment to I level, and recommend clinical application of the CDK4/6 inhibitor combined endocrine treatment in HR+/HER 2-advanced breast cancer.
However, with the widespread use of CDK4/6 inhibitors in the clinic, the problem of drug resistance is increasingly pronounced. Drug resistance occurs in almost all breast cancer patients: first line therapy treatment produces resistance for 24-28 months, and second line therapy is shorter, greatly limiting the clinical use of CDK4/6 inhibitors. How to overcome the drug resistance of CDK4/6 inhibitors is a urgent problem to be solved.
WO2021139817A1 discloses a CDK inhibitor compound a, of the formula (I):
however, the therapeutic effect of this compound on tumors (especially CDK4/6 inhibitor resistant tumors) is under investigation.
Disclosure of Invention
The application provides an anti-tumour use of the CDK inhibitor compound A. The inventor of the present application unexpectedly found in the study that the compound A has good therapeutic effect on tumors, in particular CDK4/6 inhibitor resistant tumors, and can be used for preparing related medicaments.
In a first aspect, the present application provides the use of a compound a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound a, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a tumour, said compound a having the structure shown in formula (I):
in a second aspect, the application provides a method of treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of compound a described above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound a or a pharmaceutically acceptable salt thereof. In some embodiments, the individual is a subject or patient in need of treatment.
In a third aspect, the present application provides a compound a or a pharmaceutically acceptable salt thereof as described above, or a pharmaceutical composition or medicament comprising said compound a or a pharmaceutically acceptable salt thereof, for use in the treatment of a tumour.
In a fourth aspect, the present application provides an antitumor pharmaceutical composition comprising the above compound a or a pharmaceutically acceptable salt thereof, and a clinically/pharmaceutically acceptable other drug.
In a fifth aspect, the present application provides the use of compound a or a pharmaceutically acceptable salt thereof as described above in combination with a clinically/pharmaceutically acceptable other medicament for the manufacture of an antitumor medicament.
In a sixth aspect, the application provides a method of treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof described above, or a pharmaceutical composition comprising said compound a or a pharmaceutically acceptable salt thereof, and a clinically/pharmaceutically acceptable other drug.
In some embodiments, the tumor described in the first to sixth aspects above is selected from a sensitive tumor or a drug resistant tumor.
In some embodiments, the tumor described in the first to sixth aspects above is a drug resistant tumor. In specific embodiments, the resistant tumor is selected from a primary resistant tumor or a secondary resistant tumor.
In some embodiments, the sensitive tumor or drug resistant tumor is selected from breast cancer, liver cancer, melanoma, or acute myeloid leukemia. In some embodiments, the breast cancer is selected from hr+/HER 2-breast cancer, triple negative breast cancer, HR-/her2+ breast cancer. In some embodiments, the acute myeloid leukemia is myelogenous monocytic leukemia. In some specific embodiments, the tumor is melanoma.
In some embodiments, the resistant tumor is a CDK4/6 inhibitor resistant tumor. In some specific embodiments, the CDK4/6 inhibitor resistant tumor is selected from CDK4/6 inhibitor primary resistant tumors or CDK4/6 inhibitor acquired resistant tumors. In some specific embodiments, the CDK4/6 inhibitor is selected from the group consisting of piperacillin Bai Xili (Palbociclib), abbe's eli (Abemaciclib), rebaudimide (Ribociclib), darcy (Dalpiciclib), preferably piperacillin Bai Xili.
In some embodiments, the CDK4/6 inhibitor resistant tumor is selected from breast cancer or liver cancer. In a preferred embodiment, the CDK4/6 inhibitor resistant tumour is selected from breast cancer or liver cancer that is resistant to Palbociclib, for example breast cancer or liver cancer that is resistant to the primary of Palbociclib, breast cancer or liver cancer that is resistant to the acquired of Palbociclib. In a more preferred embodiment, the breast cancer that is resistant to Palbociclib primary, or resistant to Palbociclib acquired is selected from hr+/HER 2-breast cancer, triple negative breast cancer, or HR-/her2+ breast cancer that is resistant to Palbociclib primary or acquired.
In some embodiments, compound a or a pharmaceutically acceptable salt thereof described in the first to sixth aspects above is administered to a subject or patient in need of treatment in a clinically acceptable manner, e.g. orally, by injection, topically, etc., preferably orally.
In some embodiments, the pharmaceutical composition described in the first to sixth aspects above comprises compound a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In some embodiments, the compound a or a pharmaceutically acceptable salt thereof is formulated into a clinically acceptable pharmaceutical dosage form, such as an oral formulation, an injectable formulation, an external formulation, and the like, preferably an oral formulation. In some embodiments, the medicament contains pharmaceutically acceptable excipients or excipients. In some embodiments, each dosage unit of the medicament contains compound a, or a pharmaceutically acceptable salt thereof, in an amount of 1mg to 1000mg, preferably 5mg to 500mg, 10mg to 300mg, 20 to 200mg, 20 to 150mg, or 25mg to 100mg, calculated as compound a, e.g., each dosage unit contains compound A1 mg, 5mg, 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 300mg, etc. The medicament of the application can be administered in a single dose or in divided doses.
In some embodiments, compound a or a pharmaceutically acceptable salt thereof described in the first to sixth aspects above is administered to a subject or patient in need of treatment in a therapeutically effective amount to treat a tumor. By a therapeutically effective amount is meant an amount that alleviates, inhibits tumor growth or eliminates tumors, benefits the subject or patient, but does not cause intolerable toxic side effects.
In some embodiments, the therapeutically effective amount (based on compound a) is from 1 mg/day to 1000 mg/day. In preferred embodiments, the therapeutically effective amount may be from 5 mg/day to 500 mg/day, from 10 mg/day to 300 mg/day, from 20 mg/day to 300 mg/day, or from 25 mg/day to 250 mg/day. The therapeutically effective amounts may be administered once a day (QD) or divided into multiple administrations within a day, for example divided into twice a day (BID) or three times a day (TID), as a total daily dose. The therapeutically effective amounts may also be administered at intervals, for example, once every 2-7 days, or once every 2-4 weeks, or once every 1-3 months, or continuously for 1-3 weeks, followed by 1 week of discontinuation.
In some embodiments, the pharmaceutical composition described in the first to sixth aspects above further comprises a further clinically/pharmaceutically acceptable drug, for example a further anti-tumour drug. In particular embodiments, the other drug is an endocrine therapeutic drug, such as anastrozole, letrozole, exemestane, tamoxifen, toremifene, fulvestrant, megestrol, fluoxymesterone, or ethinyl estradiol, and the like. In a preferred embodiment, the endocrine therapeutic agent is fulvestrant.
In some embodiments, compound a or a pharmaceutically acceptable salt thereof described in the first to sixth aspects above may be administered as monotherapy or with other anti-tumour agents, biological therapy, radiation therapy and/or traditional Chinese medicine therapy which are clinically/pharmaceutically acceptable. In some embodiments, the other antineoplastic agent is an endocrine therapeutic agent, such as anastrozole, letrozole, exemestane, tamoxifen, toremifene, fulvestrant, megestrol, fluoxymesterone, or ethinyl estradiol. In a preferred embodiment, the endocrine therapeutic agent is fulvestrant.
In some embodiments, the other agents described in the fourth to sixth aspects above, for example other antineoplastic agents, may be included in the same formulation unit as compound a or a pharmaceutically acceptable salt thereof, or may be included in different formulation units, in the form of a combined package, for example a kit product. In some embodiments, the additional drug is selected from endocrine therapeutic drugs, such as anastrozole, letrozole, exemestane, tamoxifen, toremifene, fulvestrant, megestrol, fluoxymesterone, or ethinyl estradiol. In a preferred embodiment, the endocrine therapeutic agent is fulvestrant.
In order to provide a more concise description, some quantitative data herein do not use the term "about. It is to be understood that each numerical value given herein, whether explicitly or implicitly using the term "about," is intended to include not only the actual given value (the given value), but also to include approximations of such given value based on reasonable inferences of one of ordinary skill in the art, including equivalents and approximations of such given value due to experimental and/or measurement conditions. The approximation is preferably + -20%, + -15%, + -10%, + -8%, + -6%, + -5%, + -4%, + -3%, 2%, + -1% on the basis of the given values.
The term "pharmaceutically acceptable carrier" as used herein refers to a carrier that does not interfere with the biological activity of the active ingredient, including those conventionally used in the pharmaceutical arts. The pharmaceutically acceptable carrier of the present application may be solid or liquid, including pharmaceutically acceptable excipients, buffers, emulsifiers, stabilizers, preservatives, diluents, encapsulating agents, fillers, and the like.
"Individual" as used herein refers to mammals, including but not limited to primates, cows, horses, pigs, sheep, goats, dogs, cats, and rodents such as rats and mice.
The "sensitivity" refers to good response of tumor cells after the tumor cells are contacted with the medicine, and the good response is represented by obviously reduced proliferation speed of the tumor cells, apoptosis or death of the tumor cells, growth stopping of the tumor, reduction or disappearance of the tumor volume and the like.
The term "drug resistance" as used herein refers to the tolerance of tumor cells to antitumor drugs. Types of tumor cell resistance can be divided into: ① Congenital drug resistance, also known as primary drug resistance, and intrinsic drug resistance, refers to the fact that tumor cells are insensitive to an anti-tumor drug at the initial stage of treatment or when they are first contacted with the drug. ② Acquired drug resistance: tumor cells begin to be sensitive to the drug and have better effect in the first treatment, but do not respond to the drug after a period of treatment, so that the curative effect is obviously reduced or eliminated. Once tumor resistance is established, the drug cannot exert an anticancer effect. Even if a large portion of tumor cells are killed, the remaining small portion of drug-resistant cells continue to grow, causing recurrence of the cancer and failure of subsequent chemotherapy.
In the present description and claims, the words "comprise," "comprising," and "include" are intended to mean "including but not limited to," and are not intended to exclude other moieties, additives, components, or steps.
In some embodiments, compound a of the application has nanomolar inhibition of CDK2, CDK4, CDK6, CDK9 kinase activity. The preclinical test results show that the compound A has good anti-tumor activity in various human tumor cells and mice in-vivo transplanted tumor models of breast cancer piperaquine Bai Xili drug-resistant strains (including primary drug resistance and acquired drug resistance), breast cancer piperaquine Bai Xili sensitive strains, liver cancer, melanoma, acute myeloid leukemia and the like. Therefore, the compound A has good clinical application prospect in treating advanced malignant tumors (including but not limited to breast cancer, liver cancer, melanoma, acute myelogenous leukemia and the like), and provides a new drug choice for treating CDK4/6 inhibitor resistant tumors.
Drawings
FIG. 1 shows the inhibition of the growth of the cell transplantation tumor by Compound A on the drug-resistant strain xMCF-7/Palbo-R obtained from the drug-resistant strain of piperaquine Bai Xili.
FIG. 2 shows the inhibition of cell transplantation tumor growth by compound A against the primary drug-resistant strain MDA-MB-468 of piperaquine Bai Xili.
FIG. 3 shows the inhibition of MCF-7 cell transplantation tumor growth by Compound A.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials are presented herein for illustrative purposes only.
The drugs, test materials, cell lines, test animals, etc., referred to in the following embodiments are commercially available or prepared by conventional methods in the art.
EXAMPLE 1 test of Compound A Selective inhibitory Activity against CDK2/4/6/9 in vitro
Compound a was tested for its inhibition constant K i on 7 kinases, CDK2/CyclinA2, CDK2/CyclinE1, CDK4/CyclinD3, CDK6/CyclinD1, CDK6/CyclinD3, CDK9/CyclinT1, using the Mobility assay (Mobility SHIFT ASSAY) method.
1. Detection method
1) Compound a was diluted with 100% dmso and the highest concentration of compound a for the different kinase activity inhibition assays was as follows, 2-fold dilution, giving a total of 7 concentration gradients:
2) 200nL of Compound A solution was transferred into 384 well plates using ECHO550, and multiplex well assays were performed for each concentration.
3) ATP solution was prepared using kinase buffer. The highest ATP concentrations used for the different kinase activity inhibition assays were as follows, 2.5-fold dilutions, 6 concentration gradients total:
4) Transfer 10 μl of ATP solution into 384 well plates, each concentration of compound a was cross-combined with a different concentration of ATP. Solvent control wells were simultaneously set up, compound a solution was replaced with equal volumes of solvent DMSO, and ATP was added at different concentrations.
5) Preparing a 2-fold kinase and substrate mixed solution: a kinase buffer was used to prepare a kinase and substrate mixed solution. Transfer 10. Mu.L of the mixed solution into 384 well plates and mix well with shaking at 450 rpm.
6) Incubation was carried out at 28℃for 60min, and the reaction was stopped by adding 25. Mu.L of stop solution to each well of 384-well plate, and centrifuging at 1000rpm for 1min.
7) The conversion data is read at CaliperEZ ReaderII.
8) Data were imported GRAPHPAD PRISM version 6.0 and curve fitted using Mix model inhibition mode. Fitting formulas VmaxApp =vmax/(1+i/(Alpha X K i)),KmApp＝Km*(1+I/Ki)/(1+I/(Alpha*Ki)) and y= VmaxApp X/(KmApp +x). Wherein X refers to substrate concentration; y refers to enzyme concentration; i refers to inhibitor concentration; k i denotes the inhibition constant; alpha values determine the competitive mechanism: if Alpha is around 1, the compound is in a non-competitive relationship with the substrate; if Alpha is very large, the compound is in a competitive relationship with the substrate; if Alpha is very small but greater than 0, the compound is in an anti-competing relationship with the substrate.
2. Test results
The results show that the compound A has strong inhibition effect on all 7 kinases. Ki values of less than 200nM for CDK2/CyclinE 1; for other kinases, ki values were less than 50nM and competitive inhibitory compounds were found on all 7 targets tested.
TABLE 1 test results of in vitro test for Selective inhibitory Activity of Compound A against CDK2/4/6/9 Ki
Ki(nM) Alpha
CDK2/CyclinA2 41.4 ～4.9×1015
CDK2/CyclinE1 164.3 ～7.4×1016
CDK4/CyclinD1 10.2 2.5
CDK4/CyclinD3 1.4 68.7
CDK6/CyclinD1 1.7 34.5
CDK6/CyclinD3 10.7 57.0
CDK9/CyclinT1 25.4 51.7
EXAMPLE 2 investigation of proliferation inhibition of tumor cells in vitro by Compound A (CTG assay)
Cell lines such as human breast cancer, liver cancer, melanoma, acute myelogenous leukemia and the like are selected to study the activity of the compound A for inhibiting the proliferation of tumor cells in vitro. After 4-7 days of incubation with different concentrations of compound a and control, cellTiter-Glo (CTG) assay was performed to evaluate cell viability and calculate IC 50.
1. Test method
The tumor cell lines were cultured in an incubator at 37℃with 5% CO 2. Cells in the logarithmic growth phase were taken for plating at regular passages. Cell staining was performed with trypan blue and living cells were counted. The cell concentration was adjusted to the appropriate concentration. Cell suspension was added to each well of the culture plate, and cell-free culture medium was added to the blank wells. The plates were incubated overnight at 37℃in an incubator with 5% CO 2 and 100% relative humidity. Compound a was diluted with DMSO from highest concentration gradient to lowest concentration (20 μm, 1:3 dilution, 8 concentration gradients, 3 duplicate wells per concentration gradient), and compound working fluid was added to the cell culture plate; solvent control wells were added with the same final concentration of DMSO. And (5) putting the mixture back into an incubator for culturing for 4 to 7 days. Cell viability was measured according to the instructions of the Promega CellTiter-Glo (CTG) luminescence cell viability assay kit (Promega-G7573).
The Inhibition Rate (IR) of the test compound was calculated using the following formula:
IR(％)＝[1–(RLU Compounds of formula (I) –RLU Blank control )/(RLU vehicle control –RLU Blank control )]×100％
Inhibition rates of compounds at different concentrations were calculated in Excel, and then the inhibition graphs were plotted using GRAPHPAD PRISM software and relevant parameters were calculated, including minimum inhibition rate, maximum inhibition rate, and IC 50. IC 50 is calculated by the following formula.
Y=minimum inhibition + (maximum inhibition-minimum inhibition)/(1+10 ((LogIC 50 -X) HillSlope))
X: log (concentration)
Y: reaction value, numerical value and X negative correlation
HillSlope: slope factor
Note that: when the maximum inhibition rate is < 50%, the result is expressed as IC 50 > the maximum initial concentration.
2. Test results
The results in Table 2-1 show that compound A has good inhibitory activity against the 7 breast cancer cell lines tested and has significant advantages over the CDK4/6 selective inhibitor piperaquine Bai Xili. Wherein, the inhibition activity of the compound A on the primary drug-resistant strain MDA-MB-468 (Rb-), the obtained drug-resistant strain xMCF-7/Palbo-R of the piperazine Bai Xili is better than that of the piperazine Bai Xili, especially the inhibition activity of the compound A on the primary drug-resistant strain MDA-MB-468 (Rb-), the advantage of the compound A is more obvious, the maximum inhibition rate exceeds 99%, and the maximum inhibition rate of the piperazine Bai Xi is only 34%. The inhibition activity of the compound A on the HR+/HER 2-breast cancer cells T47D, the triple negative breast cancer cells HCC1187 and MDA-MB-231 is superior to that of the piperaquin Bai Xili, and the inhibition activity of the compound A on the HR+/HER 2-breast cancer cells MCF-7 and the HR-/HER2+ breast cancer cells MDA-MB-453 is equivalent to that of the piperaquin Bai Xi. For HR-/her2+ breast cancer cells MDA-MB-453, although compound a has an IC 50 value of about 2 times that of piperaquine Bai Xili, compound a can achieve a maximum inhibition of about 100% on this cell line, whereas piperaquine Bai Xili can only achieve a maximum inhibition of about 74% even with increasing doses. Compound a also showed higher maximal inhibition in other breast cancer cell lines. It can be seen that compound a has a greater advantage over piperaquine Bai Xili in terms of the maximal effect of inhibiting tumor cell proliferation.
As a direct target downstream of CDK4/6, rb protein is considered a major biomarker for assessing CDK4/6 inhibitor sensitivity, and Rb protein deficiency (Rb-) suggests that the tumor is not sensitive (primary resistance) to CDK4/6 inhibitors. The results in Table 2-2 show that the compound A has remarkable inhibition effect on Hep3B (Rb-) liver cancer cells, and the maximum inhibition rate is more than 99%, which suggests that the compound A has good treatment effect on CDK4/6 inhibitor resistant liver cancer.
In addition, the results in Table 2-2 show that: the compound A also has good inhibitory activity on acute myelogenous leukemia cells MV-4-11, MOLM-13 and melanoma cells SK-MEL-5, and the maximum inhibition rate is over 99 percent.
Table 2-1 in vitro proliferation inhibition IC 50 values (CTG test) of Compound A on multiple breast cancer cells
Table 2-2 in vitro proliferation inhibition IC 50 values (CTG test) of Compound A on multiple human tumor cells
EXAMPLE 3 in vivo efficacy test of Compound A in mice with human Breast cancer piprazole Bai Xili-derived drug-resistant Strain xMCF-7/Palbo-R cell transplantation tumor
The piperacillin Bai Xili resistant human breast cancer xMCF-7/Palbo-R cell is a CDK4/6i acquired resistant breast cancer cell line induced by piperacillin Bai Xili for a long time in vitro, and has the characteristics of CCNE amplification, rb protein expression reduction and the like similar to clinical patients.
1. Test method
The cell is cultured in vitro in monolayer by adding 10% foetal calf serum and 1% penicillin/streptomycin into DMEM/F12 medium, and culturing in incubator with 5% CO 2 at 37deg.C. Passaging was performed twice a week with conventional digestion treatments with pancreatin-EDTA. When the saturation of the cells is 80% -90% and the number reaches the requirement, the cells are collected, counted and inoculated. An estrogen pellet (0.36 mg) was inoculated onto the left back of each mouse 3 days before cell inoculation, 0.2mL (1X 10 7) of xMCF-7/Palbo-R cells (with matrigel, volume ratio 1:1) were inoculated subcutaneously onto the right back of each mouse, and group administration was started when the average tumor volume reached about 158mm 3. The specific groups and methods of administration are shown in Table 3.
2. Observing and evaluating index
2.1 Tumor volume
After animals were grouped, tumor length and diameter were measured twice a week.
① Tumor volume: v=1/2×a×b 2
② Relative tumor volume:
③ Relative tumor volume proliferation rate:
④ Tumor inhibition rate:
Note that: v: tumor volume
A: tumor major diameter b: short diameter of tumor
RTV: relative tumor volume
TV nd: tumor volume on day n
TV 1d: tumor volume on day 1
RTV xnd: the nth balance was all tumor volumes
TV Xn: dose group nth balance average tumor volume
TV X1: tumor volume of drug administration group 1 balance
TV Mn: solvent set nth balance average tumor volume
TV M1: solvent set 1 st balance average tumor volume
2.2 Tumor weight
After euthanasia of the animals CO 2, the tumors were dissected and weighed.
Inter-group tumor weight differences: tumor weight inhibition ratio = (1-dose tumor weight/solvent tumor weight) ×100% of the tumor weight of the group
2.3 Statistical analysis
(1) And (3) data acquisition: and measuring and observing according to the requirements of a test scheme, recording and storing in a computer database.
(2) Statistical analysis: data processing statistical analysis was performed between groups using statistical software SPSS19.0, with a significance level set to P <0.05. Comparisons between two groups were analyzed using T-test and comparisons between three or more groups were analyzed using One-way ANOVA. If the F values have significant differences, a Games-Howell method is used for analysis; if there is no significant difference in the F values, the Dunnet (2-side) method is used for analysis.
3. Test results
The results show that: compound A (30, 50, 70 mg/kg) can obviously inhibit xMCF-7/Palbo-R cell transplantation tumor growth after being administrated by gastric lavage for 21 days continuously for 1 time daily, the tumor growth inhibition rates (TGI) are 72.1%, 75.8% and 80.2%, and the effective dose is less than or equal to 30mg/kg. At the same molar dose as 70mg/kg of compound a, 55mg/kg of piperacillin Bai Xi had no significant tumor inhibiting effect (tgi=19.3%). It can be seen that compound A has good inhibition effect on CDK4/6 inhibitor acquired drug resistant tumors.
TABLE 3 influence of Compound A on xMCF-7/Palbo-R cell transplantation tumor growth (mean+ -SEM, n=10)
Note that: *** P <0.001, compared to the solvent group. D21: 21 days after administration.
Example 4 in vivo efficacy test of Compound A in mice with human breast cancer Pepper Bai Xili primary drug resistant strain MDA-MB-468 cell transplantation tumor
MDA-MB-468 cells are triple negative breast cancer cells and Rb expression is negative (Rb-), and therefore may be insensitive to CDK4/6 inhibitors (intrinsic drug resistance/primary drug resistance). In vitro cell drug sensitivity assay results show that compound a has an inhibitory effect on MDA-MB-468 cells with IC 50 on the order of 10 -7 M, whereas CDK4/6 selective inhibitor pimple Bai Xili has little inhibitory effect on the cells.
The experiment adopts a NOD SCID mouse human breast cancer MDA-MB-468 cell xenograft tumor model, compares the in-vivo tumor inhibition effect of the compound A and the piperaquine Bai Xili on Rb-breast cancer, and simultaneously examines the dose-effect relationship of the tumor inhibition effect of the compound A.
Resuscitates and passages (passage 11) MDA-MB-468 cells to the desired cell number, dilutes the cells with serum-free medium and matrigel (1:1), counts with a cytometer, adjusts the tumor cell number to about 1X 10 8/mL, and places the cell suspension in an ice bath. The MDA-MB-468 cell suspension was extracted by a sterile syringe and inoculated into the subcutaneous tissue on the right back of the NOD SCID mouse, the inoculation volume was 0.1 mL/mouse, and about 1X 10 7 tumor-containing cells were contained, so as to prepare a model of the NOD SCID mouse MDA-MB-468 transplanted tumor. When the tumor volume is up to about 105mm 3, mice with good tumor growth are selected, and animals are evenly grouped according to the tumor volume. The grouping and administration methods are shown in Table 4. The observation and evaluation indexes are the same as in example 3.
The results show that the compound A (30, 50, 70 mg/kg) can inhibit MDA-MB-468 cell transplantation tumor growth in a dose-dependent manner by being continuously administrated by gastric lavage for 28 days 1 time a day, has good dose-effect relationship, and has the effective dose less than or equal to 50mg/kg, wherein the TGI is 56.7%, 89.9% and 102.2% respectively. At the same molar dose as 70mg/kg of Compound A, 55mg/kg of piperacillin Bai Xi has no remarkable tumor inhibiting effect, and the TGI is only 14.8%. It can be seen that compound a has a significant inhibitory effect on tumors that are primary resistant to CDK4/6 inhibitors.
Table 4 effect of compound a on tumor growth in MDA-MB-468 cell transplantation tumor (mean±sem, n=7
Note that: **P<0.01,*** P <0.001, compared to the solvent group. D28: 28 days after administration.
EXAMPLE 5 in vivo efficacy test of Compound A in mice with human breast cancer MCF-7 cell transplantations
The in vitro monolayer culture of the human breast cancer MCF-7 cells is carried out by adding 2mM glutamine+1% non-essential amino acid (NEAA) +10% fetal bovine serum, 1% penicillin/streptomycin/amphotericin B into EMEM (EBSS) culture medium, and culturing in a incubator at 37 ℃ with 5% CO 2. Passaging was performed twice a week with conventional digestion treatments with pancreatin-EDTA. When the saturation of the cells is 80% -90% and the number reaches the requirement, the cells are collected, counted and inoculated. An estrogen pellet (0.36 mg) was inoculated on the left back of each mouse 3 days before cell inoculation, 0.2mL (1X 10 7) of MCF-7 cells (with matrigel, volume ratio 1:1) were inoculated subcutaneously on the right back of each mouse, and the drug effect experiment was started when the average tumor volume reached about 190mm 3. The grouping and administration methods are shown in Table 5. The observation and evaluation indexes are the same as in example 3.
The results show that the compound A (30, 50, 70 mg/kg) can inhibit the growth of MCF-7 cell transplantation tumor in a dose-dependent manner after being continuously administrated by gastric lavage for 21 days, and TGI is 87.9%, 108.6% and 115.2%, respectively, and has good dose-effect relationship, and the effective dose is less than or equal to 30mg/kg. The tumor inhibiting effect of 30-70 mg/kg of compound A is better than that of 55mg/kg of piperaquine Bai Xili (the equimolar dosage of the compound A is 70 mg/kg). It can be seen that for non-drug resistant tumors, the tumor-inhibiting effect of compound a is better than that of piperaquine Bai Xili at the same molar concentration. Moreover, the compound A30mg/kg group achieves better curative effect under the condition that the molar concentration is less than half of that of the pimple Bai Xili (55 mg/kg). The tumor inhibiting effect of the compound A is obviously better than that of the piperaquine Bai Xili on the breast cancer sensitive to the CDK4/6 inhibitor.
Table 5 effect of compound a on MCF-7 cell transplantation tumor growth (mean±sem, n=8)
Note that: **P<0.01,*** P <0.001, compared to the solvent group. D21: 21 days after administration.
EXAMPLE 6 in vivo efficacy test of Compound A in mice with human myelomonocytic leukemia MV-4-11 cell transplantation tumor
Resuscitates and passages MV-4-11 cells to the required cell number, dilutes the cells with serum-free medium, counts the cells with a cell counter, adjusts the tumor cell number to about 1X 10 8/mL, and places the cell suspension in ice bath. To facilitate tumor formation in NOD/SCID mice after being vaccinated with MV-4-11 cells, the mice were intraperitoneally injected with cyclophosphamide at a dose of 100mg/kg and a dosing volume of 10mL/kg the day prior to vaccination. Inoculating the same day sterile syringe to extract MV-4-11 cell suspension, inoculating it into the axillary subcutaneous tissue of right forelimb of NOD/SCID mouse, and preparing NOD/SCID mouse MV-4-11 transplantation tumor model with 0.1 mL/mouse and tumor cell content of about 1×10 7. On day 14 after inoculation, when the tumor volume is about 120mm 3 as the average value, selecting mice with good tumor growth, and uniformly grouping and dosing the animals according to the tumor volume. The grouping and administration methods are shown in Table 7. The observation and evaluation indexes are the same as in example 3.
The results show that the compound A (15, 25, 50 mg/kg) can inhibit the growth of MV-4-11 cell transplantation tumor in a dose-dependent manner for 14 days after being continuously administrated by gastric lavage for 1 time per day, and the TGI is respectively 50.6%, 87.4% and 109.6%, so that the compound A has good dose-effect relationship, and the effective dose is less than or equal to 25mg/kg.
Table 6 Effect of Compound A on tumor growth in MV-4-11 cell transplantation tumor (mean+ -SEM, n=7)
Note that: *P<0.05,**P<0.01,*** P <0.001, compared to the solvent group. D14: 14 days after administration.
It should be understood that while the application has been described in connection with the above specific forms, it is not intended to be limited to the specific form set forth herein. It will be obvious to those skilled in the art that various equivalent changes can be made to the technical features contained in the application as described without departing from the spirit of the application, and these changes shall fall within the scope of the application.

Claims (10)

1. Use of compound a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound a or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a tumor, wherein the structure of said compound a is represented by formula (I):
Wherein the tumor is selected from a sensitive tumor or a drug resistant tumor.
2. The use of claim 1, wherein the tumor is a drug resistant tumor selected from a primary drug resistant tumor or a secondary drug resistant tumor.
3. The use of claim 1 or 2, wherein the sensitive or resistant tumor is selected from breast cancer, liver cancer, melanoma or acute myeloid leukemia.
4. The use of claim 3, wherein the breast cancer is selected from hr+/HER 2-breast cancer, triple negative breast cancer or HR-/her2+ breast cancer; and/or the acute myeloid leukemia is myelogenous monocytic leukemia.
5. The use of any one of claims 1-3, wherein the resistant tumor is a CDK4/6 inhibitor resistant tumor, the CDK4/6 inhibitor resistant tumor being selected from a CDK4/6 inhibitor primary resistant tumor or a CDK4/6 inhibitor acquired resistant tumor.
6. Use according to claim 5 wherein the CDK4/6 inhibitor is selected from piperacillin Bai Xili (Palbociclib), abbe's eli (Abemaciclib), rebaudimide (Ribociclib) or darcy (Dalpiciclib), preferably piperacillin Bai Xili.
7. The use according to claim 5 or 6, wherein the CDK4/6 inhibitor resistant tumour is selected from breast cancer or liver cancer, preferably breast cancer or liver cancer resistant to piperaquine Bai Xili, more preferably breast cancer or liver cancer resistant to piperaquine Bai Xili primary, or breast cancer or liver cancer resistant to piperaquine Bai Xili acquired; preferably, the breast cancer that is resistant to piperaquine Bai Xili primary or acquired is selected from hr+/HER 2-breast cancer, triple negative breast cancer or HR-/her2+ breast cancer that is resistant to piperaquine Bai Xili primary or acquired.
8. The use according to any one of claims 1 to 7, wherein compound a or a pharmaceutically acceptable salt thereof is formulated into a clinically acceptable pharmaceutical dosage form, such as an oral formulation, an injectable formulation, an external formulation, etc., preferably an oral formulation.
9. The use according to any one of claims 1 to 8, wherein each dosage unit of the medicament contains compound a or a pharmaceutically acceptable salt thereof in an amount of 1mg to 1000mg, preferably 5mg to 500mg, 10mg to 300mg, 20 to 200mg, 20 to 150mg or 25mg to 100mg calculated as compound a, e.g. each dosage unit contains compound A1mg, 5mg, 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 75mg, 100mg, 150mg, 200mg, 250mg or 300mg.
10. The use according to any one of claims 1-9, wherein said compound a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound a or a pharmaceutically acceptable salt thereof, is used in combination with a clinically/pharmaceutically acceptable other medicament for the preparation of said medicament;
The other drug is preferably an endocrine treatment drug; preferably, the endocrine therapeutic agent is selected from anastrozole, letrozole, exemestane, tamoxifen, toremifene, fulvestrant, megestrol, fluoxytestosterone or ethinyl estradiol, more preferably fulvestrant.
CN202311791586.3A 2022-12-26 2023-12-25 Application of CDK inhibitor Pending CN118252835A (en)

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