Application of combination of estrogen receptor degradation agent and CDK4 / 6 kinase inhibitor in preparation of medicine for treating breast cancer

Abstract

The invention provides application of combination of an estrogen receptor degradation agent and a CDK4 / 6 kinase inhibitor in preparation of a medicine for treating breast cancer. Specifically, the invention provides application of a compound shown in a formula (I) or pharmaceutically acceptable salt of the compound in combination with a CDK 4 / 6 kinase inhibitor in preparation of a medicine for treating breast cancer. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to the use of an estrogen receptor (ER) degrader in combination with a CDK4 / 6 kinase inhibitor in a medicament for treating breast cancer, and belongs to the field of pharmaceuticals. Background Art

[0002] Estrogen receptor-positive (ER+) breast cancer is the most common subtype of breast cancer, and endocrine therapy is the main treatment for ER+ breast cancer. Although endocrine therapy has greatly reduced the recurrence rate and mortality of breast cancer, primary resistance and secondary resistance remain major challenges. Therefore, there is a continuous need to discover better drugs and drug combinations to address the issue of drug resistance. WO2021139756A discloses a new class of ER degraders that can effectively inhibit the proliferation of MCF7 cells and their mutants. Summary of the Invention

[0003] The present disclosure provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with a CDK 4 / 6 kinase inhibitor in the preparation of a medicament for treating breast cancer.

[0004]

[0005] In some embodiments, the breast cancer is estrogen receptor-positive (ER+) breast cancer.

[0006] In some embodiments, the breast cancer is estrogen receptor-positive (ER+), HER-2 negative breast cancer.

[0007] In some embodiments, the breast cancer is estrogen receptor-positive (ER+), HER-2 negative metastatic or locally advanced breast cancer.

[0008] In some embodiments, the breast cancer is ESR1-mutated breast cancer.

[0009] In some embodiments, the CDK 4 / 6 kinase inhibitor is Palbociclib.

[0010] In some embodiments, the CDK 4 / 6 kinase inhibitor is Ribociclib.

[0011] In some embodiments, the CDK 4 / 6 kinase inhibitor is Abemaciclib.

[0012] In some embodiments, the CDK 4 / 6 kinase inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

[0013]

[0014] In some embodiments, the CDK 4 / 6 kinase inhibitor is the hydroxyethyl sulfonate salt of the compound represented by formula (II).

[0015] In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) is a phosphate salt.

[0016] In some embodiments, the pharmaceutically acceptable salt of the compound represented by formula (I) is a triphosphate salt, and the specific structure is as shown in formula (III) below,

[0017]

[0018] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof disclosed herein is selected from 1 - 1000 mg, and the optional doses are 1 mg, 5 mg, 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, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg,805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg or 1000 mg, or a value between any two of these point values, and the dosing frequency is once daily or twice daily.

[0019] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 50 mg, 150 mg, 300 mg, 600 mg or 900 mg, and the dosing frequency is once daily or twice daily.

[0020] In an alternative embodiment, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, and the dosing frequency is once daily or twice daily.

[0021] In an alternative embodiment, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 150 mg, and the dosing frequency is once daily or twice daily.

[0022] In an alternative embodiment, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 300 mg, and the dosing frequency is once daily or twice daily.

[0023] In an alternative embodiment, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 600 mg, and the dosing frequency is once daily or twice daily.

[0024] In an alternative embodiment, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 900 mg, and the dosing frequency is once daily or twice daily.

[0025] In some embodiments, for the uses provided in the present disclosure, the administered dose of the CDK 4 / 6 kinase inhibitor is selected from 1 - 1000 mg, and the specific administered dose can be selected from 5 mg, 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, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg or 500 mg, and the administration frequency is once a day or twice a day.

[0026] In some embodiments, the administered dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 1 - 500 mg, and the administration frequency is selected from once a day or twice a day.

[0027] In some embodiments, the administered dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg or 200 mg, and the administration frequency is once a day or twice a day.

[0028] In some embodiments, the administered dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof in the present disclosure is selected from 75 mg, 100 mg, 125 mg, 150 mg or 175 mg, and the administration frequency is once a day or twice a day.

[0029] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to the present disclosure is selected from 100 mg, 125 mg, or 150 mg, and the frequency of administration is once or twice a day.

[0030] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to the present disclosure is 100 mg, and the frequency of administration is once a day.

[0031] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to the present disclosure is 125 mg, and the frequency of administration is once a day.

[0032] In some embodiments, the dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof according to the present disclosure is 150 mg, and the frequency of administration is once a day.

[0033] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from 50 mg, 150 mg, 300 mg, 600 mg, or 900 mg, and the frequency of administration is once a day. The dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and the frequency of administration is once a day.

[0034] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, and the frequency of administration is once a day. The dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and the frequency of administration is once a day.

[0035] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 150 mg, and the frequency of administration is once a day. The dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and the frequency of administration is once a day.

[0036] In some embodiments, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 300 mg, and the frequency of administration is once a day. The dosage of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and the frequency of administration is once a day.

[0037] In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 600 mg, and the administration frequency is once a day. The administration dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and the administration frequency is once a day.

[0038] In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 900 mg, and the administration frequency is once a day. The administration dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, and the administration frequency is once a day.

[0039] In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, and the administration frequency is once a day. The administration dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 125 mg, 150 mg, or 175 mg, and the administration frequency is once a day.

[0040] In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 150 mg, and the administration frequency is once a day. The administration dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 125 mg, 150 mg, or 175 mg, and the administration frequency is once a day.

[0041] In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 300 mg, and the administration frequency is once a day. The administration dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 125 mg, 150 mg, or 175 mg, and the administration frequency is once a day.

[0042] In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 600 mg, and the administration frequency is once a day. The administration dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 125 mg, 150 mg, or 175 mg, and the administration frequency is once a day.

[0043] In some embodiments, the dose of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is 900 mg, and the administration frequency is once a day. The administration dose of the compound represented by formula (II) or a pharmaceutically acceptable salt thereof is selected from 125 mg, 150 mg, or 175 mg, and the administration frequency is once a day.

[0044] In some embodiments, the administered dose of abemaciclib is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, and the frequency of administration is once or twice a day.

[0045] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 50 mg, 150 mg, 300 mg, 600 mg or 900 mg, and the frequency of administration is once a day. The administered dose of abemaciclib is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, and the frequency of administration is once or twice a day.

[0046] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, and the frequency of administration is once a day. The administered dose of abemaciclib is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, and the frequency of administration is once or twice a day.

[0047] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 150 mg, and the frequency of administration is once a day. The administered dose of abemaciclib is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, and the frequency of administration is once or twice a day.

[0048] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 300 mg, and the frequency of administration is once a day. The administered dose of abemaciclib is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, and the frequency of administration is once or twice a day.

[0049] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 600 mg, and the dosing frequency is once a day. The dosing dose of Abemaciclib is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, and the dosing frequency is once a day or twice a day.

[0050] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 900 mg, and the dosing frequency is once a day. The dosing dose of Abemaciclib is selected from 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg or 600 mg, and the dosing frequency is once a day or twice a day.

[0051] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 50 mg, 150 mg, 300 mg, 600 mg or 900 mg, and the dosing frequency is once a day. The dosing dose of Abemaciclib is selected from 100 mg or 200 mg, and the dosing frequency is twice a day.

[0052] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 50 mg, and the dosing frequency is once a day. The dosing dose of Abemaciclib is selected from 100 mg or 200 mg, and the dosing frequency is twice a day.

[0053] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 150 mg, and the dosing frequency is once a day. The dosing dose of Abemaciclib is selected from 100 mg or 200 mg, and the dosing frequency is twice a day.

[0054] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 300 mg, and the dosing frequency is once a day. The dosing dose of Abemaciclib is selected from 100 mg or 200 mg, and the dosing frequency is twice a day.

[0055] In some embodiments, the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 600 mg, and the dosing frequency is once a day. The dosing dose of Abemaciclib is selected from 100 mg or 200 mg, and the dosing frequency is twice a day.

[0056] In some embodiments, the dose of the compound represented by formula (I) or its pharmaceutically acceptable salt is 900 mg, and the administration frequency is once a day. The administration dose of Abemaciclib is selected from 100 mg or 200 mg, and the administration frequency is twice a day.

[0057] In some embodiments, one administration cycle of the compound represented by formula (I) or its pharmaceutically acceptable salt is 28 days, with continuous administration for 28 days.

[0058] In some embodiments, one administration cycle of the CDK4 / 6 kinase inhibitor is 28 days, during which administration is carried out for the first 21 days and stopped for the last 7 days.

[0059] On the other hand, the present disclosure provides a pharmaceutical composition comprising the compound represented by formula (I) or its pharmaceutically acceptable salt, a CDK4 / 6 kinase inhibitor, and at least one pharmaceutically acceptable excipient, and the excipient includes but is not limited to a filler, a disintegrant, a binder or a lubricant.

[0060] The pharmaceutical composition described in the present disclosure can be prepared into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections, suppositories, inhalants or sprays, etc.

[0061] The administration route of the combination described in the present disclosure is selected from oral administration, parenteral administration, and transdermal administration, and the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.

[0062] In the present disclosure, breast cancer patients can be selected from those with one of the following menopause states:

[0063] a) Having undergone bilateral oophorectomy in the past, or age ≥ 60 years; or

[0064] b) Age < 60 years, in a state of natural menopause (defined as spontaneous cessation of regular menstruation for at least 12 consecutive months without other pathological or physiological reasons), with estradiol and FSH at postmenopausal levels; or

[0065] c) Premenopausal or perimenopausal patients, but must receive LHRH agonist treatment during the study.

[0066] In the present disclosure, breast cancer patients have progressed after at least 1 line of endocrine therapy in the previous advanced stage; and have received ≤ 2 lines of chemotherapy for advanced diseases in the past.

[0067] In the present disclosure, the breast cancer patients have at least one extracranial measurable lesion that meets RECIST v1.1.

[0068] The "combination" described in the present disclosure is a mode of administration. Taking the combination of ER degrader and CDK4 / 6 kinase inhibitor as an example, it means that at least one dose of ER degrader and at least one dose of CDK4 / 6 kinase inhibitor are administered within a certain time period, wherein the two drugs have a pharmacological effect at least at a certain time point or a certain period of time. Since some drugs have a long half-life, the two drugs can be administered at a longer time interval, and the effect of pharmacological action occurring at a certain time point or a certain period of time can still be achieved. The time limit or interval depends on the half-life of the drug, for example, it can be preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. ER degrader and CDK4 / 6 kinase inhibitor can be administered simultaneously or sequentially. The combination includes administering ER degrader and CDK4 / 6 kinase inhibitor by the same administration route or different administration routes. The combined administration mode described in the present disclosure is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.

[0069] The progression-free survival (PFS) described in this disclosure is the time from randomization to the date of the first documented objective tumor progression or to death due to any cause, whichever occurs first.

[0070] The overall survival (OS) described in this disclosure refers to the period from the randomization period to the period of death caused by any cause. For subjects who are still alive at the last follow-up, their OS is calculated as data loss based on the last follow-up time. For subjects who have been lost to follow-up, their OS is calculated as data loss based on the last confirmed survival time before loss of follow-up. The OS of data loss is defined as the time from randomization to censoring.

[0071] The objective response rate (ORR) described in this disclosure refers to the proportion of patients whose tumors shrink to a certain extent and remain for a certain period of time, including cases of CR and PR. The solid tumor response evaluation criteria (RECIST1.1 criteria) are used to assess the objective response of tumors. The subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable (SD), and progressive (PD) according to the RECIST 1.1 criteria.

[0072] The disease control rate (DCR) described in the present disclosure refers to the percentage of confirmed complete remission, partial remission and disease stable (≥8 weeks) cases among patients who can be evaluated for efficacy.

[0073] Complete remission (CR) as described in the present disclosure: all target lesions disappear, and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10 mm.

[0074] Partial remission (PR) as described in the present disclosure: The sum of the diameters of the target lesions is reduced by at least 30% compared to the baseline level.

[0075] Disease progression (PD) as described in the present disclosure: With reference to the minimum value of the sum of the diameters of all measured target lesions throughout the entire experimental study process, the relative increase in the diameter sum is at least 20% (if the baseline measurement is the minimum, the baseline value is used as the reference); in addition, it must be satisfied that the absolute value of the diameter sum increases by at least 5 mm (the appearance of one or more new lesions is also regarded as disease progression).

[0076] Disease stability (SD) as described in the present disclosure: The degree of reduction of the target lesions does not reach the level of PR, and the degree of increase does not reach the level of PD, and it is between the two. The minimum value of the diameter sum can be used as a reference during the study. Description of the Drawings

[0077] Figure 1 . Effect of the administered compound on the tumor volume of transplanted tumors in MCF-7 tumor-bearing mice.

[0078] Figure 2 . Efficacy of the administered compound on transplanted tumors in MCF-7 tumor-bearing mice - tumor weight ***: p < 0.001, vs Vehicle. Detailed Description of the Invention

[0079] The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

[0080] Example 1. Efficacy of Drug A (the compound shown in formula (III), which can be prepared by referring to the method in WO2021139756A) alone and in combination with Drug B (hydroxyethyl sulfonate of the compound shown in formula (II), which can be prepared by referring to the method in WO2014183520A) in a breast cancer animal model of human breast cancer cells MCF-7

[0081] 1.1 Drug Information

[0082] Drug A was provided by Jiangsu Hengrui Medicine Co., Ltd.;

[0083] Drug B was provided by Jiangsu Hengrui Medicine Co., Ltd.;

[0084] The estrogen sustained-release tablets, with a release time of 60 days, 100 tablets, 0.36 mg / tablet, were purchased from Innovative research of America.

[0085] 1.2 Experimental Animals and Cells

[0086] Scid Beige mice, SPF, 12 - 14 g, ♀, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Arrival date: November 24, 2020, License number: SCXK(Beijing)2016 - 0006.

[0087] Human breast cancer cell line MCF - 7 was provided by the Molecular Cell Department of Shanghai Hengrui.

[0088] 1.3 Drug preparation

[0089] Drug A was formulated into 1, 3, 10 mg / ml (free base) aqueous solutions with 9% PEG400 + 0.5% Tween - 80 + 90.5% (0.5% CMC - Na) aqueous solution, and the dosing doses were 10, 30, 100 mg / kg respectively; once a day, the oral gavage volume was 10 ml / kg.

[0090] Drug A was used in combination with Drug B, and 10 mg / ml Drug A and 25 mg / ml Drug B were administered orally respectively.

[0091] Vehicle was 9% PEG400 + 0.5% Tween - 80 + 90.5% (0.5% CMC - Na) aqueous solution, once a day, and the oral gavage volume was 10 ml / kg.

[0092] 1.4 Experimental methods

[0093] Tumor cell transplantation

[0094] One day before inoculation, an estrogen - releasing tablet (0.36 mg, 60 - day release) was implanted subcutaneously on the left side of the mice. MCF - 7 cells (5×10 6 cells, containing 50% MatrixGel) 200 μL were inoculated subcutaneously on the right rib of 120 Scid Beige mice. After 12 days of inoculation, mice with excessive or too small body weight and tumor size were removed. According to the tumor volume, the mice were randomly divided into 6 groups, with 8 mice in each group, as shown in Table 1. Administer the drugs for 18 days, measure the tumor volume twice a week, weigh the mice, and record the data. The grouping and drug administration are shown in Table 1. 3 After that, the mice with excessive or too small body weight and tumor size were removed. According to the tumor volume, the mice were randomly divided into 6 groups, with 8 mice in each group, as shown in Table 1. Administer the drugs for 18 days, measure the tumor volume twice a week, weigh the mice, and record the data. The grouping and drug administration are shown in Table 1.

[0095] Table 1. Experimental grouping and drug administration

[0096]

[0097] Record data using Excel statistical software: the average value is calculated as avg; the SD value is calculated as STDEV; the SEM value is calculated as STDEV / SQRT(number of animals in each group); use GraphPad Prism software to plot graphs, and use Two-way ANOVA, One-way ANOVA, and t-test for statistical analysis of the data.

[0098] The formula for calculating the tumor volume (V) is: V = 1 / 2 × L 长 × L 短 2

[0099] The relative tumor proliferation rate T / C (%) = (T - T0) / (C - C0) × 100, where T and C are the tumor volumes of the treatment group and the control group at the end of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment.

[0100] The tumor inhibition rate TGI (%) = 100 - T / C (%).

[0101] The growth inhibitory effect of the administered compound on MCF-7 tumors is shown in Table 2 and Figure 1 as follows. By the 18th day of administration, compared with the Vehicle group (Group 1), all administered groups could significantly inhibit the growth of MCF-7 tumors (p < 0.001). The tumor inhibition rates of Drug A at doses of 10, 30, and 100 mg / kg were 91%, 102%, and 113% respectively, and the tumor inhibition effect was dose-dependent. The tumor inhibition rate of Drug B at 25 mg / kg was 83%. When Drug A at 10 mg / kg was co-administered with Drug B at 25 mg / kg, the tumor inhibition rate was 114%, which was significantly higher than that of the single-agent groups (p < 0.001). The tumors of each group of mice were dissected and weighed, and the tumor weights of all administered groups were significantly smaller than those of the Vehicle group (p < 0.001), as Figure 2 shown.

[0102] During the administration process, 1 mouse in the Vehicle group died on the 14th day, and the body weight of 1 mouse decreased by more than 15%. The reason may be the toxic effect after inoculating the estrogen-releasing tablets, and the physical condition of individual mice was relatively poor. The average body weights of the mice in all administered groups did not decrease significantly, indicating that the compounds at the current administered doses had no obvious toxic effects. The growth inhibitory effect of the administered compound on MCF-7 (Y537S) tumors is shown in Table 2 and Figure 1 as follows.

[0103] In summary, the combined use of Drug A and the CDK4 / 6 kinase inhibitor Drug B can further enhance the tumor inhibition effect.

[0104] Table 2. Efficacy of the administered compound on MCF-7 (Y537S) mouse transplanted tumors

[0105] Grouping Average Tumor Volume D1 Average Tumor Volume D18 TGI (%) P vs Blank P vs Combo 1 192.62±11.47 795.89±68.55 2 184.56±12.17 236.92±19.93 91％ P＜0.001 P＜0.001 3 182.22±8.37 169.87±7.30 102％ P＜0.001 4 184.52±9.69 107.55±29.70 113％ P＜0.001 5 187.33±11.30 292.64±29.70 83％ P＜0.001 P＜0.001 6 184.32±10.73 100.10±16.77 114％ P＜0.001 。

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a CDK 4 / 6 kinase inhibitor in the preparation of a medicament for treating breast cancer.

2. The use according to claim 1, wherein the breast cancer is estrogen receptor positive (ER+) breast cancer.

3. The use according to claim 2, wherein the breast cancer is HER-2 negative breast cancer.

4. The use according to claim 1, wherein the breast cancer is metastatic or locally advanced breast cancer.

5. The use according to claim 1, wherein the breast cancer is ESR1 mutant breast cancer.

6. The use according to claim 1, wherein the CDK 4 / 6 kinase inhibitor is selected from Palbociclib, Ribociclib, Abemaciclib or a compound of formula (II) or a pharmaceutically acceptable salt thereof. Preferably, the CDK 4 / 6 kinase inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt thereof.

7. The use according to claim 6, wherein the pharmaceutically acceptable salt of the compound of formula (II) is hydroxyethylsulfonate.

8. The use according to any one of claims 1 to 7, wherein the pharmaceutically acceptable salt of the compound of formula (I) is phosphate, preferably, the pharmaceutically acceptable salt of the compound of formula (I) is triphosphate.

9. The use according to any one of claims 1 to 7, wherein the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 1 - 1000 mg, and the administration frequency is once a day or twice a day; preferably, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 50 mg, 150 mg, 300 mg, 600 mg or 900 mg, and the administration frequency is once a day.

10. The use according to any one of claims 6 to 8, wherein the administration dose of the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from 1 - 500 mg, and the administration frequency is selected from once a day or twice a day; preferably, the administration dose of the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from 75 mg, 100 mg, 125 mg, 150 mg or 175 mg, and the administration frequency is once a day; most preferably, the administration dose of the compound of formula (II) or a pharmaceutically acceptable salt thereof is selected from 100 mg, 125 mg or 150 mg, and the administration frequency is once a day.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, the CDK4 / 6 kinase inhibitor as described above, and at least one pharmaceutically acceptable excipient.

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