CN113840608B - Use of CDK4/6 inhibitors in combination with VEGFR inhibitors for the preparation of a medicament for the treatment of tumors - Google Patents

Use of CDK4/6 inhibitors in combination with VEGFR inhibitors for the preparation of a medicament for the treatment of tumors Download PDF

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CN113840608B
CN113840608B CN202080038010.8A CN202080038010A CN113840608B CN 113840608 B CN113840608 B CN 113840608B CN 202080038010 A CN202080038010 A CN 202080038010A CN 113840608 B CN113840608 B CN 113840608B
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inhibitor
cdk4
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CN113840608A (en
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张岚
林侃
廖成
张连山
孙飘扬
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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

Abstract

Use of a CDK4/6 inhibitor in combination with a VEGFR inhibitor in the preparation of a medicament for treating a neoplastic disease. Specifically, the CDK4/6 inhibitor is a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof, and the VEGFR inhibitor is apatinib or a pharmaceutically acceptable salt thereof.

Description

Use of CDK4/6 inhibitors in combination with VEGFR inhibitors for the preparation of a medicament for the treatment of tumors
The present application claims priority from chinese patent application CN201910460310.4, the filing date of which is 2019, 5, 30. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The application relates to an application of a CDK4/6 inhibitor and a VEGFR inhibitor in combination in preparing medicines for treating tumor diseases.
Background
Breast cancer is one of the most common malignant tumors in women, with about 130 thousands of new cases worldwide each year. In China, the incidence of breast cancer accounts for 7% -10% of the incidence of various malignant tumors of the whole body, accounts for 18% of all female tumors, the number of domestic patients is over 50 ten thousand at present, the incidence rate of the breast cancer is rapidly increased, the first female tumor incidence spectrum is already listed in some large cities, and nearly 50% of patients relapse and metastasize after treatment. In recent years, with the progress of research of tumor molecular biology, molecular targeted therapy is more and more widely applied in breast cancer therapy and achieves more remarkable curative effects, and the molecular targeted therapy becomes a brand new therapy mode after three traditional modes of operation, radiotherapy and chemotherapy, and is also a hot spot of research in the field of current breast cancer therapy.
Cyclin-dependent kinases (CDKs) are a class of serine/threonine kinases that phosphorylate downstream protein molecules by forming dimers with the corresponding Cyclin, thereby promoting orderly progression through the phases of the cell cycle, allowing cell growth and proliferation. Currently, a variety of CDK4/6 selective inhibitors have been marketed in clinical trials or batches including Palbociclib from the company of pyroxene, ribociclib from the company of North, abemaciclib from the company of Gift, and the like.
WO2014183520 discloses a CDK4/6 inhibitor of the formula (I) having a chemical name of 6-acetyl-8-cyclopentyl-5-methyl-2- ((5- (piperidin-4-yl) pyridin-2-yl) amino) pyrido [2,3-d ] pyrimidin-7 (8H) -one with remarkable CDK4/6 inhibitory activity and high selectivity,
WO2016124067A discloses isethionates of compounds of formula (I) above and a process for their preparation.
There has been much research on the use of CDK4/6 inhibitors in combination with other drugs, WO2017193141a discloses that CDK4/6 inhibitors in combination with EGFR inhibitors can be used to treat triple negative breast cancer; WO2016024-232A discloses a method of treating cancer by combining a CDK4/6 inhibitor with a BTK kinase inhibitor; lori S.Hart et al in "Preclinical Therapeutic Synergy of MEK/2 and CDK4/6 Inhibition in Neuroblastoma" found that CDK4/6 inhibitors and MEK inhibitors have synergistic effects for preclinical use in neuroblastoma; CN103781480a discloses that a combination of a CDK4/6 inhibitor and an FGFR kinase inhibitor can be used to treat cancer; bollard et al, "Palbociclib (PD-0332991) a selective CDK4/6 inhibitor,restricts tumour growth in preclinical models of hepatocellular carcinoma" disclose that Palbociclib alone or in combination with sorafenib may be a new strategy for treating hepatocellular carcinoma; CN106029097a discloses that the combination of abemaciclib and ramucirumab can be used to treat non-small cell lung cancer; CN108883182a discloses that abemaciclib and ramucirumab in combination can be used to treat mantle cell lymphoma.
There is currently little research on the use of CDK4/6 inhibitors in combination with small molecule VEGFR inhibitors for the treatment of cancer.
Disclosure of Invention
The application provides an application of a CDK4/6 inhibitor and a VEGFR inhibitor in combination in preparing medicines for treating tumor diseases.
The CDK4/6 inhibitor disclosed by the application can be selected from a compound shown in a formula (I) or pharmaceutically acceptable salt thereof,
in the present application, the pharmaceutically acceptable salts of the compounds of formula (I) are selected from the group consisting of hydrochloride, phosphate, hydrogen phosphate, sulfate, bisulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate, p-toluenesulfonate, methanesulfonate, isethionate, maleate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate or laurylsulfonate, preferably isethionate, having the structure shown in formula (II),
in alternative embodiments, the VEGFR inhibitor is selected from the group consisting of VEGFR-2 inhibitors, preferably the VEGFR-2 inhibitor is apatinib or a pharmaceutically acceptable salt thereof.
In some embodiments, the pharmaceutically acceptable salt of apatinib is selected from the group consisting of mesylate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malate, hydrochloride, hydrobromide, sulfate, and phosphate, and in preferred embodiments, the pharmaceutically acceptable salt of apatinib is mesylate.
In alternative embodiments, the VEGFR inhibitor is apatinib mesylate.
The neoplastic disease described in the present application is selected from sarcomas, lymphomas, lung cancer, bronchogenic cancer, prostate cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic cholangiocarcinoma, hepatocellular carcinoma, adrenal cancer, gastric tumor, glioma, glioblastoma, endometrial cancer, melanoma, renal cancer, renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myelogenous leukemia, brain tumor, brain cancer, oral cavity cancer, pharyngeal cancer, laryngeal cancer, small intestine cancer, non-hodgkin's lymphoma, melanoma, colon adenoma, neoplasm, epithelial cancer, breast cancer, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, neoplastic disease, neck or head tumor, primary thrombocythemia, myelogenous fibrosis and megaloblastic leukemia, preferably breast cancer, hepatocellular carcinoma, colon cancer.
In an alternative embodiment, the breast cancer is hormone receptor positive breast cancer.
In an alternative embodiment, the breast cancer is a triple negative breast cancer.
In an alternative embodiment, the breast cancer is her2 positive breast cancer.
In an alternative embodiment, the CDK4/6 inhibitor is administered in a dose selected from the group consisting of 1-500mg, preferably 50-200mg, more preferably 100-150mg, administered once a day, twice a day, preferably once a day.
In alternative embodiments, the CDK4/6 inhibitor is administered in a dose of 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, preferably 100mg, 125mg or 150mg, at a frequency of once a day, twice a day, preferably once a day.
In alternative embodiments, the VEGFR inhibitor is administered at a dose of 100-500mg at a frequency of once daily, two days of stopping for five days, and seven days of stopping for seven days.
In alternative embodiments, the VEGFR inhibitor is dosed at 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 500mg, preferably 250mg or 375mg, administered once a day, two days of five days of dosing, seven days of dosing.
In alternative embodiments, the CDK4/6 inhibitor is administered in a dose selected from 100mg, 125mg, or 150mg, once daily, and the VEGFR inhibitor is administered in a dose of 250mg or 375mg, once daily, two days of five days of administration, and seven days of administration.
In alternative embodiments, the CDK4/6 inhibitor is administered at a dose of 100mg once daily, and the VEGFR inhibitor is administered at a dose of 250mg or 375mg once daily, for two days five days, for seven days.
In alternative embodiments, the CDK4/6 inhibitor is administered at a dose of 125mg once daily, and the VEGFR inhibitor is administered at a dose of 250mg or 375mg once daily, for two days five days, for seven days.
In alternative embodiments, the CDK4/6 inhibitor is administered at a dose of 150mg once daily, and the VEGFR inhibitor is administered at a dose of 250mg or 375mg once daily, for two days five days, for seven days.
The routes of use described herein include, but are not limited to, oral administration, parenteral administration, transdermal administration, including, but not limited to, intravenous injection, subcutaneous injection, intramuscular injection.
The present application provides a method of treating a neoplastic disease comprising administering to a subject a therapeutically effective amount of a CDK4/6 inhibitor as described above and a VEGFR inhibitor.
The application provides a pharmaceutical composition comprising a CDK4/6 inhibitor as described above, a VEGFR inhibitor and one or more pharmaceutically acceptable excipients, diluents or carriers.
The term "combination" as used herein refers to a mode of administration, meaning that at least one dose of a CDK4/6 inhibitor and a VEGFR inhibitor is administered over a period of time, wherein both agents exhibit pharmacological effects. The period of time may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. The CDK4/6 inhibitor and the VEGFR inhibitor may be administered simultaneously or sequentially. Such a period includes treatment wherein the CDK4/6 inhibitor, VEGFR inhibitor is administered by the same route of administration or by different routes of administration.
Drawings
Figure 1. Weight change of xxt47d xenograft model tumor-bearing mice after administration of test subjects;
fig. 2. Relative weight change of xxt47d xenograft model tumor-bearing mice after administration of test subjects;
FIG. 3 shows the growth curves of the tumors of each group.
Detailed Description
The application will be further described with reference to the following examples, which are not intended to limit the scope of the application.
EXAMPLE 1 in vivo pharmacodynamic Studies of Compounds of formula (I) isethionate (drug A) alone or in combination with apatinib mesylate (drug B) on xxT47D human breast cancer cells (ER+, HER 2-) subcutaneous xenograft tumor BALB/c nude mouse model
1. Experimental materials
Drug A was prepared using the method disclosed in WO 2016124067A;
mice: strain: BALB/c nude mice; week and body weight: 6-8 weeks old, 18-22 g weight; gender: a female; quantity: 42 (excluding the remaining mice in groups); the suppliers: shanghai Sipuler-BiKai laboratory animal Co., ltd.
Cell source: xxT47D tumor cells A cell line was established by in vitro isolation of xenograft tumors constructed from parental T47D tumor cells (source: ATCC, HTB-133).
2. Experimental methods and procedures
1) Establishment of xxT47D breast cancer model
xxT47D tumor cells are established by in vitro isolation of xenograft tumors constructed from parental T47D tumor cells, and the same procedure is performed 2 times. In vitro wall-attached culture of xxT47D tumor cells under the conditions of adding 10% fetal bovine serum, 100U/ml penicillin and streptomycin 100 μg/ml into RPMI 1640 medium, and 5% CO at 37 DEG C 2 Culturing. Passaging was performed twice a week with conventional digestion treatments with pancreatin-EDTA. When the saturation of the cells is 80% -90%, the cells are collected, counted and inoculated.
2) Tumor cell inoculation
Estrogen tablets (0.18 mg/tablet) were inoculated subcutaneously into the left back of each mouse, after three days, 0.2mL (10X 10e6 cells+Matrigel, volume ratio 1:1) of xxT47D cells were inoculated subcutaneously into the right back of each mouse, and the average tumor volume reached 173mm 3 The administration of the groups was started according to the experimental design (table 1).
TABLE 1 grouping of experimental animals and dosing regimen
Note that: n: number of mice per group; dosing volume: based on the weight of the mice, 10. Mu.l/g. If the weight loss exceeds 15%, the dosing regimen should be adjusted accordingly, (Vehicle A+vehicle B) is the solvent group.
3) Test drug configuration
TABLE 2 test drug configuration
4) The experimental index is to examine whether tumor growth is inhibited, retarded or cured. Tumor diameters were measured twice weekly with vernier calipers. The calculation formula of the tumor volume is: v=0.5a×b 2 A and b represent the major and minor diameters of the tumor, respectively.
The tumor-inhibiting effect of the compound was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = (1- (mean tumor volume at the end of the treatment group administration-mean tumor volume at the beginning of the treatment group administration))/(mean tumor volume at the end of the treatment with the solvent control group-mean tumor volume at the beginning of the treatment with the solvent control group) () x 100%.
Tumor weights will be measured after the end of the experiment and the T/C weight percentages calculated, tweight and Cweight representing tumor weights in the dosing group and vehicle control group, respectively.
Statistical analysis, including mean and Standard Error (SEM) of tumor volumes at each time point for each group. The treatment group showed the best treatment effect at day 21 after dosing at the end of the trial, so the statistical analysis was performed to evaluate the inter-group differences based on this data. The comparison between two groups was analyzed by T-test, the comparison between three or more groups was analyzed by one-way ANOVA, and if there was a significant difference in F values, the test was performed using the Games-Howell method. If there is no significant difference in the F values, the Dunnet (2-side) method is used for analysis. All data analysis was performed with SPSS 17.0. p < 0.05 was considered a significant difference. 3. Experimental results
1) Weight change
The effect of subject treatment on the body weight of xxT47D tumor-bearing mice is shown in figures 1 and 2.
2) Tumor volume change
The change in tumor volume of each group following treatment with the xxT47D tumor-bearing mice is shown in table 3.
TABLE 3 tumor volumes at various time points for each group
Note that: a. mean ± SEM; b. days after administration
3) Tumor growth curve
The growth curves of the tumors of each group are shown in FIG. 3.
4) Evaluation index of antitumor drug effect
TABLE 4 evaluation of tumor-inhibiting efficacy of drug A and drug B on xxT47D xenograft tumor models (calculated based on tumor volume at day 21 post-dose)
Note that: a. mean ± sem.b. tumor growth inhibition was determined by T/C and TGI (%) = [1- (T) 21 -T 0 )/(V 21 -V 0 )]X 100) calculation. c.p values were calculated from tumor volumes.
TABLE 5 gravimetric analysis of drug A and drug B group tumors
Note that: a. mean ± SEM. b. Tumor growth inhibition was calculated from T/C weight = TW treatment/TW control. c.p values were calculated from tumor weights.
4. Discussion of experiments
21 days after the start of administration, the average tumor volume of the solvent control group tumor-bearing mice reached 1283mm 3 25mg/kg of the test object, the drug A and 50mg/kg of the drug B have average tumor volumes of 724mm respectively 3 And 704mm 3 Has remarkable tumor inhibiting effect (p-value is 0.019 and 0.015 respectively) compared with the solvent control group.
The average tumor volume of the 25mg/kg drug A-in combination with 50mg/kg drug B-treated group was 354mm 3 The mean differences were significant (p < 0.001) compared to the solvent group, the combination groups showed stronger antitumor activity compared to the respective single drug groups, and the differences were significant, and the p-values of drug a and drug B combination groups were 0.022 and 0.003, respectively, compared to the single drug. The tumor weight results (table 5) are substantially identical to the tumor volume results.
Taken together, drug a and drug B alone showed significant anti-tumor activity on the xxT47D human breast cancer xenograft tumor model at the experimental protocol doses. Compared with single medicine, the combined application of medicine A and medicine B can further enhance the anti-tumor effect.
While particular embodiments of the present application have been described above, it will be appreciated by those skilled in the art that these are merely illustrative, and that many changes and modifications may be made to these embodiments without departing from the principles and spirit of the application. Accordingly, the scope of the application is defined by the appended claims.

Claims (13)

1. Use of a CDK4/6 inhibitor in combination with a VEGFR inhibitor for the manufacture of a medicament for the treatment of a tumour disease, said CDK4/6 inhibitor being a compound of formula (I) or a pharmaceutically acceptable salt thereof,
the VEGFR inhibitor is apatinib or pharmaceutically acceptable salt thereof, and the tumor disease is breast cancer.
2. The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (I) is isethionate.
3. The use of claim 1, wherein the VEGFR inhibitor is apatinib mesylate.
4. The use of claim 1, wherein the breast cancer is hormone receptor positive breast cancer.
5. Use according to claim 1, wherein the CDK4/6 inhibitor is administered in an amount selected from 1-500mg, at a frequency of once a day or twice a day.
6. The use according to claim 5, wherein the CDK4/6 inhibitor is administered in an amount selected from 50-200mg, at a frequency of once a day or twice a day.
7. The use according to claim 5, wherein the CDK4/6 inhibitor is administered in an amount selected from the group consisting of 100-150mg, administered once a day, twice a day.
8. The use according to claim 5, wherein the CDK4/6 inhibitor is administered in an amount of 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, at a frequency of once or twice daily.
9. The use according to claim 8, wherein the CDK4/6 inhibitor is administered at a dose of 100mg, 125mg or 150mg, at a frequency of once a day, twice a day.
10. The use of claim 5, wherein the VEGFR inhibitor is administered at a dose of 100-500mg at a frequency of once daily, twice daily, and seven days.
11. The use of claim 10, wherein the VEGFR inhibitor is dosed at 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 500mg, administered once a day, for two days five days, for seven days.
12. The use of claim 11, wherein the VEGFR inhibitor is administered at a dose of 250mg or 375mg once a day, for two days five days of administration, for seven days of administration.
13. A pharmaceutical composition comprising a CDK4/6 inhibitor as defined in any one of claims 1-12, a VEGFR inhibitor and one or more pharmaceutically acceptable excipients.
CN202080038010.8A 2019-05-30 2020-05-29 Use of CDK4/6 inhibitors in combination with VEGFR inhibitors for the preparation of a medicament for the treatment of tumors Active CN113840608B (en)

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