WO2021063332A1 - 一种ezh2抑制剂与cdk4/6抑制剂联合在制备治疗肿瘤药物中的用途 - Google Patents

一种ezh2抑制剂与cdk4/6抑制剂联合在制备治疗肿瘤药物中的用途 Download PDF

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WO2021063332A1
WO2021063332A1 PCT/CN2020/118612 CN2020118612W WO2021063332A1 WO 2021063332 A1 WO2021063332 A1 WO 2021063332A1 CN 2020118612 W CN2020118612 W CN 2020118612W WO 2021063332 A1 WO2021063332 A1 WO 2021063332A1
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cancer
tumor
inhibitor
cdk4
day
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PCT/CN2020/118612
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张岚
廖成
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江苏恒瑞医药股份有限公司
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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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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

Definitions

  • the present disclosure relates to the use of a combination of an EZH2 inhibitor and a CDK4/6 inhibitor in preparing drugs for treating tumors, and belongs to the field of pharmacy.
  • Breast cancer is one of the most common malignant tumors in women. There are approximately 1.3 million new cases worldwide each year. In my country, the incidence of breast cancer accounts for 7%-10% of the incidence of various malignant tumors throughout the body, and about 18% of all female tumors. At present, the number of patients in China has exceeded 500,000, and its incidence is increasing rapidly. It has been ranked first in the spectrum of female tumor incidence, and nearly 50% of patients have recurrence and metastasis after treatment. In recent years, with the deepening of tumor molecular biology research, molecular targeted therapy has become more and more widely used in the treatment of breast cancer and has achieved more significant curative effects. It has become the first after the three traditional modes of surgery, radiotherapy and chemotherapy. This new treatment model is also a hot spot in the field of breast cancer treatment.
  • the histone methyltransferase encoded by the EZH2 gene is the catalytic component of the polycomb inhibitory complex 2 (PRC2).
  • PRC2 polycomb inhibitory complex 2
  • EZH2 inhibitors have entered the clinical development stage.
  • Tazemetostat EPZ-6438 developed by Eisai is used to treat non-Hodgkin B-cell lymphoma. It is currently in phase II clinical phase.
  • CPI developed by Constellation -1205 is used to treat B-cell lymphoma and is currently in clinical phase I.
  • GSK-2816126 developed by GlaxoSmithKline is used to treat diffuse large B-cell lymphoma and follicular lymphoma and is currently in clinical phase I.
  • WO2017084494A provides an EZH2 inhibitor, the structure is as follows:
  • Cyclin-dependent kinase is a type of serine/threonine kinase that forms a dimer with the corresponding cyclin (Cyclin) to phosphorylate downstream protein molecules, thereby promoting the cell cycle Orderly progress in each phase to achieve cell growth and proliferation.
  • CDK4/6 selective inhibitors have been in clinical trials or have been approved for listing in foreign countries, including Pfizer’s Palbociclib, Novartis’s Ribociclib and Eli Lilly’s Abemaciclib.
  • WO2014183520 discloses a chemical named 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2 ,3-d]pyrimidin-7(8H)-one, the structural formula is as the CDK4/6 inhibitor shown in formula (II), it has significant CDK4/6 inhibitory activity and high selectivity.
  • PCT application WO2016124067A discloses the isethionate of the compound represented by the above formula (II) and a preparation method thereof.
  • CN109937041A discloses the use of a combination of an EZH2 inhibitor and a BTK kinase inhibitor in the preparation of a medicine for the treatment of cancer, wherein the combination optionally includes a third component, and the third component may be a CDK4/6 inhibitor. There is no report on the mechanism or related experiments of the combination of CDK4/6 inhibitor and EZH2 inhibitor.
  • the present disclosure provides a use of a combination of an EZH2 inhibitor and a CDK4/6 inhibitor in the preparation of drugs for treating tumors.
  • the EZH2 inhibitor described in the present disclosure may be selected from CPI-0209, CPI-1205, GSK126, valemetostat, tazemetostat, PF-06821497, DS-3201GSK-2816126, 3-deazaneplanocin A, HKMT-I -005, at least one of KM-301.
  • the EZH2 inhibitor described in the present disclosure is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt of the compound represented by formula (I) in the present disclosure can be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate, Valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate Acid salt, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or lauryl sulfonic acid Salt etc.
  • the administration dose of EZH2 is selected from 1 to 1600 mg, for example: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 10 mg, 15 mg
  • the dosage of EZH2 is selected from 1-800 mg, and the frequency of administration is twice a day or once a day.
  • the administration dose of EZH2 is selected from 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, administration
  • the frequency is twice a day or once a day.
  • the administration dose of EZH2 is selected from 50mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, administration
  • the frequency is twice a day.
  • the dosage of EZH2 is selected from 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, and the frequency of administration is twice a day or once a day.
  • the dosage of EZH2 is selected from 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, and the frequency of administration is twice a day.
  • the CDK4/6 inhibitor described in the present disclosure is selected from abemaciclib, ribociclib, palbociclib, alvocidib, trilaciclib, voruciclib, AT-7519, G1T-38, FLX-925, INOC-005, G1T28-1 , BPI-1178, gossypin, G1T30-1, GZ-38-1, P-276-00, staurosporine, R-547, PAN-1215, PD-0183812, AG-024322, NSC-625987, CGP-82996, PD -At least one of 171851.
  • the CDK4/6 inhibitor in the present disclosure is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt of the compound represented by formula (II) is selected from hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, malonate Acid salt, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate , Maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurel Sulfonate.
  • the CDK4/6 inhibitor is isethionate of the compound represented by formula (II).
  • the dosage of the CDK4/6 inhibitor is selected from 1-500 mg, preferably 25-200 mg, more preferably 100-175 mg, and the frequency of administration is once a day or twice a day; specifically
  • the dosage of CDK4/6 inhibitor can be 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg , 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg.
  • the dosage of the CDK4/6 inhibitor is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, and the frequency of administration is once a day or twice a day.
  • the dosage of the CDK4/6 inhibitor is selected from 75 mg, 100 mg, 125 mg or 150 mg, and the frequency of administration is once a day.
  • the EZH2 inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof
  • the CDK4/6 inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.
  • the EZH2 inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof
  • the CDK4/6 inhibitor is a compound represented by formula (II) isethionate.
  • the tumor described in the present disclosure is selected from breast cancer, ovarian cancer, endometrial cancer, kidney cancer, uterine cancer, prostate cancer, lung cancer, rectal cancer, non-small cell lung cancer, melanoma, pancreatic cancer, sarcoma, osteosarcoma, Desmofibroma, adenoid cystic carcinoma, medulloblastoma, colorectal cancer, thyroid cancer, esophageal cancer, head and neck cancer, urethral cancer, hepatocellular carcinoma, neuroendocrine tumor, glioblastoma, cholangiocarcinoma, testicular tumor , Neuroblastoma, liposarcoma, brain tumor, ureteral tumor, bladder tumor, gallbladder cancer, thyroid tumor, lymphoma, leukemia, rhabdoid tumor, synovial sarcoma, mesothelioma, cervical cancer, colon cancer, gastric cancer, brain Cancer, skin cancer, oral cancer, bone cancer, bladder cancer,
  • the tumor in the uses provided in the present disclosure is breast cancer.
  • the use provided in the present disclosure optionally further comprises other anti-tumor agents.
  • the anti-tumor agent is not a BTK kinase inhibitor.
  • the methods of combination described in the present disclosure include, but are not limited to, oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.
  • the present disclosure provides a method for treating tumors, which includes administering to a patient a therapeutically effective amount of the above-mentioned EZH2 inhibitor and CDK4/6 inhibitor.
  • Another aspect of the present disclosure provides an EZH2 inhibitor for treating tumors, which is used in combination with a CDK4/6 inhibitor.
  • Another aspect of the present disclosure provides a CDK4/6 inhibitor for the treatment of tumors, which is used in combination with an EZH2 inhibitor.
  • the patient in the method for treating tumors provided in the present disclosure, is a human.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned EZH2 inhibitor and CDK4/6 inhibitor and one or more pharmaceutically acceptable excipients, diluents or carriers.
  • the "combination" described in the present disclosure is a mode of administration, which refers to the administration of at least one dose of EZH2 inhibitor and CDK4/6 inhibitor within a certain period of time, in which both drugs show pharmacological effects.
  • the time limit may be within one administration cycle, for example, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • EZH2 inhibitors and CDK4/6 inhibitors can be administered simultaneously or in no particular order. This period includes treatments in which the EZH2 inhibitor and the CDK4/6 inhibitor are administered by the same route of administration or different routes of administration.
  • Figure 1 The body weight change curve of tumor-bearing mice in different groups.
  • Figure 2 The relative body weight change curve of different groups of tumor-bearing mice.
  • Example 1 Evaluation of CDK4/6 inhibitor (compound isethionate of formula II) and EZH2 inhibitor (compound of formula I) in xxT47D human breast cancer cell subcutaneous xenograft tumor BALB/c nude mice In vivo pharmacodynamics on the model
  • mice mouse; strain: BALB/c nude mice; age and weight: 6-8 weeks old, weighing 18-22 grams; gender: female; number: 32 (excluding the remaining mice in the group); supplier : Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
  • CDK4/6 inhibitor isethionate (drug A) of the compound represented by formula II;
  • EZH2 inhibitor compound represented by formula I (drug B).
  • xxT47D tumor cells are established by isolating xenograft tumors constructed from parental T47D tumor cells in vitro, and the establishment is completed by performing the same process twice.
  • xxT47D tumor cells were cultured adherently in vitro. The culture conditions were RPMI 1640 medium with 10% fetal bovine serum, 100U/ml penicillin and 100 ⁇ g/ml streptomycin, and cultured at 37°C with 5% CO 2. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90%, the cells are collected, counted, and seeded.
  • Estrogen tablets (0.18mg/tablet) were subcutaneously inoculated on the left back of each mouse. Three days later, 0.2mL (10 ⁇ 106 cells + Matrigel, volume ratio 1:1) xxT47D cells were subcutaneously inoculated into each mouse On the right back of the mouse, when the average tumor volume reached 185mm 3 , the drugs were administered in groups according to the experimental design (Table 1).
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the tumor diameter was measured with vernier calipers twice a week.
  • TGI total tumor growth rate
  • T/C relative tumor growth rate
  • T weight and C weight represent the tumor weight of the administration group and the vehicle control group, respectively.
  • a. Mean ⁇ SEM; b. Tumor growth inhibition is calculated by T weight / C weight TW treatment / TW vehicle ; cp value is calculated based on tumor weight.
  • the average tumor volume of the tumor-bearing mice in the solvent control group reached 714 mm 3 .
  • Test was 25mg / kg of drug A, and with 100mg / kg of drug B mean tumor volume of the two drugs in the combination group were 344mm 3 and 157mm 3, compared with the solvent control groups, exhibited significant inhibitory effect (p The values are 0.024 and 0.005), the combination group shows stronger anti-tumor activity compared with the drug A and drug B single-agent groups, and the difference is significant, with p values of 0.002 and ⁇ 0.001, respectively.
  • the average tumor volume of the test substance 100mg/kg drug B single agent was 461mm 3 , which did not show significant tumor inhibition effect compared with the solvent control group (p value is 0.112).
  • the result of tumor weight is basically consistent with the result of tumor volume.
  • drug A single agent showed significant anti-tumor activity on the xxT47D human breast cancer xenograft tumor model at the dose of the test protocol.
  • drug B can further enhance the anti-tumor effect.

Abstract

本公开涉及一种EZH2抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤药物中的用途。具体而言，本公开涉及的EZH2抑制剂选自式(I)所示化合物或其可药用盐，涉及的CDK4/6抑制剂选自式(II)所示化合物或其可药用盐。与单药相比，EZH2抑制剂与CDK4/6抑制剂联合进一步增强了抗肿瘤效果。

Description

一种EZH2抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤药物中的用途
本申请要求申请日为2019年9月30日的中国专利申请CN201910939509.5的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种EZH2抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤药物中的用途，属于药学领域。
背景技术
乳腺癌是女性最常见的恶性肿瘤之一，全世界每年约有130万新发病例。在我国，乳腺癌发病率占全身各种恶性肿瘤发病率的7％-10％，约占所有女性肿瘤的18％，目前国内患者人数已超过50万，其发病率增长迅速，在一些大城市已经位列女性肿瘤发病谱首位，并且近50％患者出现治疗后复发和转移。近年来，随着肿瘤分子生物学研究的日趋深入，分子靶向治疗在乳腺癌治疗中越来越受到广泛应用并取得了较为显著的疗效，已成为继手术、放疗和化疗三大传统模式之后一种全新的治疗模式，也是当前乳腺癌治疗领域研究的热点。
EZH2基因编码的组蛋白甲基转移酶是多梳蛋白抑制性复合体2(PRC2)的催化组分。与正常组织相比，EZH2水平在癌组织异常升高，而在癌症晚期或不良预后中，EZH2的表达水平最高。在一些癌症类型中，EZH2表达过剩与EZH2基因的扩增同时发生。大量si/shRNA实验研究发现在肿瘤细胞系中减少EZH2表达，可抑制肿瘤细胞的增殖，迁移和侵袭或血管生成，并导致细胞凋亡。
目前已有进入临床开发阶段的EZH2抑制剂，以下简要列举，卫材开发的Tazemetostat(EPZ-6438)用于治疗非霍奇金B细胞淋巴瘤，目前处于临床 II期阶段，Constellation公司开发的CPI-1205用于治疗B细胞淋巴瘤，目前处于临床I期阶段，葛兰素史克公司开发的GSK-2816126用于治疗弥漫大B细胞淋巴瘤、滤泡性淋巴瘤，目前处于临床I期阶段。
WO2017084494A中提供了一种EZH2抑制剂，结构如下所示：
Figure PCTCN2020118612-appb-000001
细胞周期蛋白依赖性激酶(Cyclin-dependent kinase,CDK)是一类丝氨酸/苏氨酸激酶，通过与相应的细胞周期蛋白(Cyclin)形成二聚体，进而磷酸化下游蛋白分子，从而推动细胞周期各时相的有序行进，实现细胞生长和增殖。目前，国外已有多种CDK4/6选择性抑制剂在临床试验阶段或已获批上市，其中包括辉瑞公司的Palbociclib、诺华公司的Ribociclib及礼来公司的Abemaciclib等。
WO2014183520公开了一种化学名为6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮，结构式如式(II)所示CDK4/6抑制剂，具有显著的CDK4/6的抑制活性和高度选择性。
Figure PCTCN2020118612-appb-000002
PCT申请WO2016124067A公开了上述式(II)所示化合物的羟乙基磺酸盐及其制备方法。
Xuejiao Song,et al(scientific reports 2016)公开一种小分子EZH2抑制剂ZLD1039性抑制可选择性阻断H3K27甲基化，并在乳腺癌中产生抗肿瘤的效果。
CN109937041A公开一种EZH2抑制剂与BTK激酶抑制剂联合用于制备治疗癌症的药物中的用途，其中该组合任选包含第三组分，所述第三组分可以是CDK4/6抑制剂。未见有关于CDK4/6抑制剂与EZH2抑制剂联合的机理或者相关实验的报道。
发明内容
本公开提供一种EZH2抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤药物中的用途。
某些实施方案中，本公开中所述的EZH2抑制剂可选自CPI-0209、CPI-1205、GSK126、valemetostat、tazemetostat、PF-06821497、DS-3201GSK-2816126、3-deazaneplanocin A、HKMT-I-005、KM-301中的至少一种。
某些实施方案中，本公开中所述EZH2抑制剂为式(I)所示化合物或其可药用盐，
Figure PCTCN2020118612-appb-000003
本公开中式(I)所示化合物可药用盐可以是盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐等。
在某些实施方案中，所述EZH2的给药剂量选自1-1600mg，例如：10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、 115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、210mg、220mg、230mg、240mg、250mg、260mg、270mg、280mg、290mg、300mg、310mg、320mg、330mg、340mg、350mg、360mg、370mg、380mg、390mg、400mg、410mg、420mg、430mg、440mg、450mg、460mg、470mg、480mg、490mg、500mg、510mg、520mg、530mg、540mg、550mg、560mg、570mg、580mg、590mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、825mg、850mg、875mg、900mg、925mg、950mg、975mg、1000mg、1025mg、1050mg、1075mg、1100mg、1125mg、1150mg、1175mg、1200mg、1225mg、1250mg、1275mg、1300mg、1325mg、1350mg、1375mg、1400mg、1425mg、1450mg、1475mg、1500mg、1525mg、1550mg、1575mg、1600mg，给药频次为一日两次或一日一次。
在某些实施方案中，所述EZH2的给药剂量选自1-800mg，给药频次为一日两次或一日一次。
在某些实施方案中，所述EZH2的给药剂量选自50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg，给药频次为一日两次或一日一次。
在某些实施方案中，所述EZH2的给药剂量选自50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg，给药频次为一日两次。
在某些实施方案中，所述EZH2的给药剂量选自150mg、200mg、250mg、300mg、350mg、400mg、450mg，给药频次为一日两次或一日一次。
在某些实施方案中，所述EZH2的给药剂量选自150mg、200mg、250mg、300mg、350mg、400mg、450mg，给药频次为一日两次。
可选的实施方案中，本公开中所述CDK4/6抑制剂选自abemaciclib、ribociclib、palbociclib、alvocidib、trilaciclib、voruciclib、AT-7519、G1T-38、 FLX-925、INOC-005、G1T28-1、BPI-1178、gossypin、G1T30-1、GZ-38-1、P-276-00、staurosporine、R-547、PAN-1215、PD-0183812、AG-024322、NSC-625987、CGP-82996、PD-171851中的至少一种。
可选的实施方案中，本公开中所述CDK4/6抑制剂为式(II)所示化合物或其可药用盐，
Figure PCTCN2020118612-appb-000004
本公开中，式(II)所示化合物的可药用盐选自盐酸盐、磷酸盐、磷酸氢盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、丙二酸盐、戊酸盐、谷氨酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、对甲苯磺酸盐、甲磺酸盐、羟乙基磺酸盐、马来酸盐、苹果酸盐、酒石酸盐、苯甲酸盐、双羟萘酸盐、水杨酸盐、香草酸盐、扁桃酸盐、琥珀酸盐、葡萄糖酸盐、乳糖酸盐或月桂基磺酸盐。
可选的实施方案中，所述CDK4/6抑制剂为式(II)所示化合物羟乙基磺酸盐。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量选自1-500mg，优选25-200mg，更优选100-175mg，给药频次为一日一次或一日两次；具体的CDK4/6抑制剂的给药剂量可以是25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量选自25mg、50mg、75mg、100mg、125mg、150mg、175mg，给药频次为一日一次或一日两次。
可选的实施方案中，所述CDK4/6抑制剂的给药剂量选自75mg、100mg、125mg或150mg，给药频次为一日一次。
可选的实施方案中，所述EZH2抑制剂为式(I)所示化合物或其可药用盐，所述CDK4/6抑制剂为式(II)所示化合物或其可药用盐。
可选的实施方案中，所述EZH2抑制剂为式(I)所示化合物或其可药用盐，所述CDK4/6抑制剂为式(II)所示化合物羟乙基磺酸盐。
本公开中所述肿瘤选自乳腺癌、卵巢癌、子宫内膜癌、肾癌、子宫癌、前列腺癌、肺癌、直肠癌、非小细胞肺癌、黑素瘤、胰腺癌、肉瘤、骨肉瘤、硬纤维瘤、腺样囊性癌、髓母细胞瘤、结肠直肠癌、甲状腺癌、食管癌、头颈癌、尿道癌、肝细胞癌、神经内分泌瘤、成胶质细胞瘤、胆管癌、睾丸瘤、神经母细胞瘤、脂肪肉瘤、脑瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、甲状腺肿瘤、淋巴瘤、白血病、横纹肌样瘤、滑膜肉瘤、间皮瘤、宫颈癌、结肠癌、胃癌、脑癌、皮肤癌、口腔癌、骨癌、膀胱癌、输卵管肿瘤、腹膜肿瘤、神经胶质瘤、胶质母细胞瘤、头颈部肿瘤、精原细胞瘤、骨髓瘤、绒毛膜上皮癌、真性红细胞增多症、多发性骨髓瘤，所述的白血病可选自急性粒细胞白血病、慢性粒细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病等；所述的淋巴瘤优选为非霍奇金淋巴瘤、弥漫大B细胞淋巴瘤或滤泡性淋巴瘤等；所述的头颈肿瘤包括上颌骨癌、喉癌、咽癌、舌癌、口内癌等。
可选的实施方案中，本公开提供的用途中所述肿瘤为乳腺癌。
可选的实施方案中，本公开中提供的用途，任选进一步包含其他抗肿瘤剂，当本公开提供的用途含有其他抗肿瘤剂时，所述的抗肿瘤剂不为BTK激酶抑制剂。
本公开所述的联用的途径包括但不限于经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
本公开提供一种治疗肿瘤的方法，包括给与患者治疗有效量的上述EZH2抑制剂和CDK4/6抑制剂。
本公开另一方面提供一种用于治疗肿瘤的EZH2抑制剂，所述EZH2抑制剂与CDK4/6抑制剂联合使用。
本公开另一方面提供一种用于治疗肿瘤的CDK4/6抑制剂，所述CDK4/6抑制剂与EZH2抑制剂联用。
可选的实施方案中，本公开提供的治疗肿瘤的方法，所述患者为人类。
本公开提供一种药物组合物，包括上述EZH2抑制剂和CDK4/6抑制剂以及一种或多种可药用的赋形剂、稀释剂或载体。
本公开中所述的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的EZH2抑制剂和CDK4/6抑制剂，其中两种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，例如4周内，3周内，2周内，1周内，或24小时以内。可以同时或不分先后顺序给予EZH2抑制剂和CDK4/6抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予EZH2抑制剂和CDK4/6抑制剂。
附图说明
图1.不同组别荷瘤鼠的体重变化曲线。
图2.不同组别荷瘤鼠相对体重变化曲线。
图3.肿瘤生长曲线。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1、评价CDK4/6抑制剂(式II所示化合物羟乙基磺酸盐)及EZH2抑制剂(式I所示化合物)在xxT47D人乳腺癌细胞皮下异种移植肿瘤BALB/c裸小鼠模型上的体内药效学
1、实验材料
1)实验动物
种属：小鼠；品系：BALB/c裸小鼠；周龄及体重：6-8周龄，体重18-22克；性别：雌性；数量：32只(不包括分组剩余鼠)；供应商：北京维通利华实验动物技术有限公司。
2)实验药物
CDK4/6抑制剂：式II所示化合物羟乙基磺酸盐(药物A)；
EZH2抑制剂：式I所示化合物(药物B)。
2、实验方法及步骤
1)xxT47D乳腺癌模型的建立
xxT47D肿瘤细胞通过亲代T47D肿瘤细胞构建的异种移植瘤体外分离建立细胞系，同样的过程进行2次而建立完成。xxT47D肿瘤细胞体外贴壁培养，培养条件为RPMI 1640培养基中加10％胎牛血清，100U/ml青霉素和100μg/ml链霉素，在37℃5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
2)肿瘤细胞接种
将雌激素片(0.18mg/片)皮下接种于每只小鼠的左后背，三天后，将0.2mL(10×106细胞+Matrigel，体积比为1:1)xxT47D细胞皮下接种于每只小鼠的右后背，肿瘤平均体积达到185mm 3时按照实验设计(表1)开始分组给药。
表1.实验动物分组及给药方案
Figure PCTCN2020118612-appb-000005
Figure PCTCN2020118612-appb-000006
注：1.N:每组小鼠数目；2.给药容积：根据小鼠体重10μl/g。如果体重下降超过15％，给药方案应做出相应调整；QD：每天一次；BID：每天两次，8小时间隔。
3)受试药物配置
表2.受试物配制方法
Figure PCTCN2020118612-appb-000007
4)实验观察、数据收集及统计分析
本实验方案的拟定及任何修改均通过了苏州药明康德新药开发有限公司实验动物管理与使用委员会(IACUC)的评估核准。实验动物的使用及福 利遵照国际实验动物评估和认可委员会(AAALAC)的规定执行。每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动，摄食摄水量(仅目测)，体重变化(每周测量两次体重)，外观体征或其它不正常情况。基于各组动物数量记录了组内动物死亡数和副作用。
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝T TV/C TV×100％(T TV：治疗组平均TV；C TV：阴性对照组平均TV)。
TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝【(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)】×100％。
在实验结束后将检测肿瘤重量，并计算T weight/C weight百分比，T weight和C weight分别表示给药组和溶媒对照组的瘤重。
统计分析，包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)。治疗组在试验结束时给药后第27天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
3、实验结果
1)死亡率、发病率及体重变化情况
实验动物的体重作为间接测定药物毒性的参考指标。在此模型中所有给药组均未显示有显著性体重下降(图1)。无发病现象。受试物治疗对xxT47D荷瘤鼠的体重影响如图1和图2所示。
2)肿瘤体积
给予xxT47D荷瘤鼠受试物治疗后各组肿瘤体积变化如表3所示，各组肿瘤的生长曲线如图3所示。
表3.各组不同时间点的瘤体积
Figure PCTCN2020118612-appb-000008
注:a.平均值±SEM；b.给药后天数
3)抗肿瘤药效评价指标
表4.药物A和药物B对xxT47D异种移植瘤模型的抑瘤药效评价(基于给药后第27天肿瘤体积计算得出)
Figure PCTCN2020118612-appb-000009
注:a.平均值±SEM.b.肿瘤生长抑制由T/C(T/C(％)＝T 27/V 27×100％)和TGI(TGI(％)＝[1-(T 27-T 0)/(V 27-V 0)]×100)计算；c.p值根据肿瘤体积计算。
表5.各组肿瘤重量分析
Figure PCTCN2020118612-appb-000010
注：a.平均值±SEM；b.肿瘤生长抑制由T weight/C weight＝TW treatment/TW vehicle计算；c.p值根据瘤重计算。
开始给药后27天，溶剂对照组荷瘤鼠的平均瘤体积达到714mm 3。受试物25mg/kg药物A以及其与100mg/kg药物B两药联用组的平均瘤体积分别为344mm 3和157mm 3，与溶剂对照组相比，均显示出显著的抑瘤作用(p值分别为0.024和0.005)，联用组与药物A和药物B单药组相比显示出更强的抗肿瘤活性，并且差异显著，p值分别为0.002和<0.001。受试物100mg/kg药物B单药平均瘤体积为461mm 3，与溶剂对照组相比未显示出显著的抑瘤作用(p值为0.112)。
肿瘤重量结果与肿瘤体积结果基本一致。
综上所述，药物A单药在试验方案剂量下在xxT47D人乳腺癌异种移植瘤模型上显示出了显著的抗肿瘤活性。与单药相比，药物A与药物B联合应用可进一步增强抗肿瘤效果。

Claims (10)

  1. 一种EZH2抑制剂与CDK4/6抑制剂联合在制备治疗肿瘤药物中的用途。
  2. 根据权利要求1所述的用途，所述EZH2抑制剂选自CPI-0209、CPI-1205、GSK126、valemetostat、tazemetostat、PF-06821497、DS-3201GSK-2816126、3-deazaneplanocin A、HKMT-I-005、KM-301或式(I)所示化合物或其可药用盐，优选式(I)所示化合物或其可药用盐，
    Figure PCTCN2020118612-appb-100001
  3. 根据权利要求1所述的用途，所述CDK4/6抑制剂选自abemaciclib、ribociclib、palbociclib、alvocidib、trilaciclib、voruciclib、AT-7519、G1T-38、FLX-925、INOC-005、G1T28-1、BPI-1178、gossypin、G1T30-1、GZ-38-1、P-276-00、staurosporine、R-547、PAN-1215、PD-0183812、AG-024322、NSC-625987、CGP-82996、PD-171851或式(II)所示化合物或其可药用盐中的至少一种，优选式(II)所示化合物或其可药用盐，
    Figure PCTCN2020118612-appb-100002
  4. 根据权利要求3所述的用途，所述CDK4/6抑制剂为式(II)所示化合物的羟乙基磺酸盐。
  5. 根据权利要求1-4任一项所述的用途，所述肿瘤选自乳腺癌、卵巢癌、子宫内膜癌、肾癌、子宫癌、前列腺癌、肺癌、直肠癌、非小细胞肺癌、黑 素瘤、胰腺癌、肉瘤、骨肉瘤、硬纤维瘤、腺样囊性癌、髓母细胞瘤、结肠直肠癌、甲状腺癌、食管癌、头颈癌、尿道癌、肝细胞癌、神经内分泌瘤、成胶质细胞瘤、胆管癌、睾丸瘤、神经母细胞瘤、脂肪肉瘤、脑瘤、输尿管肿瘤、膀胱肿瘤、胆囊癌、甲状腺肿瘤、淋巴瘤、白血病、横纹肌样瘤、滑膜肉瘤、间皮瘤、宫颈癌、结肠癌、胃癌、脑癌、皮肤癌、口腔癌、骨癌、膀胱癌、输卵管肿瘤、腹膜肿瘤、神经胶质瘤、胶质母细胞瘤、头颈部肿瘤、精原细胞瘤、骨髓瘤、绒毛膜上皮癌、真性红细胞增多症、多发性骨髓瘤中的至少一种，优选乳腺癌。
  6. 根据权利要求5所述的用途，所述EZH2抑制剂的剂量选自1-1600mg，给药频次为一日两次或一日一次。
  7. 根据权利要求6所述的用途，所述EZH2抑制剂的剂量选自150mg、200mg、250mg、300mg、350mg、400mg或450mg，给药频次为一日两次。
  8. 根据权利要求5所述的用途，所述CDK4/6抑制剂的剂量选自1-500mg，给药频次为一日一次或一日两次。
  9. 根据权利要求8所述的用途，所述的CDK4/6抑制剂的剂量选自25mg、50mg、75mg、100mg、125mg、150mg或175mg，给药频次为一日一次或一日两次。
  10. 一种药物组合物，其包含权利要求1-9任一项所述的EZH2抑制剂与CDK4/6抑制剂以及一种或多种可药用的赋形剂、稀释剂或载体。
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