CN116726022A - Application of EGFR inhibitor in preparation of medicines for treating cancers - Google Patents

Abstract

The application relates to a medical application of an EGFR inhibitor. In particular to application of a compound shown as a formula I or pharmaceutically acceptable salt thereof in preparing a medicament for treating tumors. The compound shown in the formula I or the pharmaceutically acceptable salt thereof can be used for preparing medicaments for treating tumor-related diseases.

Description

Application of EGFR inhibitor in preparation of medicines for treating cancers

Technical Field

The application belongs to the technical field of medicines, and relates to application of an EGFR inhibitor in preparation of a medicine for treating cancers.

Background

Along with the aggravation of environmental pollution, the incidence of malignant tumors increases year by year, seriously threatens human health, brings pain to patients and causes huge economic burden. Tumors are caused by abnormal proliferation of cells in the human body, and with the deep knowledge of human beings on tumors, new technologies and therapeutic means are gradually applied to clinic. The small molecule targeting drug can selectively inhibit the growth of tumor cells, has small side effects on normal cells, and has greater advantages compared with the traditional means for treating tumors.

Lung cancer is one of the most common malignant tumors, and is largely divided into non-small cell lung cancer and small cell lung cancer, with non-small cell lung cancer being the majority. Epidermal Growth Factor Receptor (EGFR) is a class of transmembrane glycoproteins present on the cell membrane of human tissue, and EGFR activates intracellular tyrosine kinase activity by binding to specific ligands, autophosphorylating some tyrosine residues at the ends, thereby activating downstream signaling pathways. Epidermal growth factor receptor plays an important role in proliferation and metabolism of cells. Because of the phenomenon that EGFR is over-expressed in tumor cells, cancer treatment drugs using EGFR as a drug target point are generated.

The first generation EGFR inhibitor represented by gefitinib has good clinical effect, but after a period of use, the T790M drug resistance mutation can be generated; in order to address drug resistant mutations, third generation EGFR inhibitors, typified by octenib, have been developed, which have become first-line drugs in NCCN clinical guidelines. After a period of time of using the octreotide, the tumor still has a high probability of generating drug-resistant mutation. The occurrence of drug resistance is mainly caused by mutation of Cys797 residues, so that the binding force between the inhibitor and kinase is broken, and the third-generation EGFR inhibitor is invalid. Therefore, there is a need to develop a novel EGFR inhibitor that is resistant to drug resistance.

Disclosure of Invention

The application aims to solve the technical problem of providing an application of an EGFR inhibitor in preparing a medicament for treating cancers, so as to solve the defect that the existing EGFR inhibitor generates drug resistance mutation, in particular EGFR-C797S drug resistance mutation.

The EGFR inhibitor is a compound shown in a formula I, and the structural formula is as follows:

the compounds of formula i are those disclosed in applicant's prior application CN 202111117969.3.

Experiments show that the compound shown in the formula I has remarkable effect of treating cancers, and particularly has good effect of treating lung cancer. Further, the curative effect on the non-small cell lung cancer is remarkable. Lung cancer is largely divided into non-small cell lung cancer (non small cell lung cancer, NSCLC) and small cell lung cancer (small celllung cancer, SCLC). Among them, non-small cell lung cancer mainly comprises lung adenocarcinoma, lung squamous cell carcinoma or lung large cell carcinoma. In non-small cell lung cancer, many driving mutations are found, common driving mutations include EGFR mutations, KRAS mutations, HER2 mutations, PIK3CA mutations, BRAF mutations, MET gene mutations or ALK gene rearrangements, ROS1 gene rearrangements, RET gene rearrangements.

The application provides application of a compound shown in a formula I or pharmaceutically acceptable salt thereof in preparing a medicament for treating cancer.

Further, the cancer according to the present application is selected from lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, blood cancer, osteosarcoma, melanoma, glioma, renal cancer, gastric cancer, liver cancer, bladder cancer, skin cancer, thyroid cancer or colorectal cancer.

In a specific embodiment of the present application, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

Further, in a specific embodiment of the present application, the non-small cell lung cancer is selected from lung adenocarcinoma, lung squamous cell carcinoma or lung large cell carcinoma.

Still further, in one embodiment of the present application, the non-small cell lung cancer is lung adenocarcinoma.

In a specific embodiment of the application, the lung cancer is selected from EGFR-mutated lung cancer, KRAS-mutated lung cancer, HER 2-mutated lung cancer, PIK3 CA-mutated lung cancer, BRAF-mutated lung cancer, MET-gene-mutated lung cancer or ALK-gene-rearranged lung cancer, ROS 1-gene-rearranged lung cancer, RET-gene-rearranged lung cancer.

Further, in a specific embodiment of the application, the EGFR mutant lung cancer is selected from EGFR-Del19 mutant lung cancer, EGFR-L858R mutant lung cancer, EGFR-C797S/T790M mutant lung cancer, EGFR-L858R/T790M mutant lung cancer, EGFR-Del19/T790M mutant lung cancer, EGFR-L858R/T790M/C797S mutant lung cancer or EGFR-Del19/T790M/C797S mutant lung cancer.

Still further, in a specific embodiment of the application, the EGFR mutant lung cancer is EGFR Del19/T790M/C797S mutant lung cancer.

The application relates to a pharmaceutical composition for treating lung cancer, which comprises a compound shown in a formula I or pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present application may be formulated according to conventional methods and may be prepared in various oral dosage forms such as tablets, pills, granules, powders, capsules, syrups, emulsions, microemulsions, etc., or in parenteral dosage forms such as injections, in particular such as intravenous infusion, subcutaneous infusion, intramuscular infusion, intraperitoneal infusion, transdermal infusion and direct infusion into tissues.

When the pharmaceutical composition of the present application is prepared in the form of an oral preparation, the ingredients known in the art may be used as pharmaceutically acceptable carriers without limitation as long as they do not interfere with the active expression of the active ingredient.

The carrier may include, for example, excipients, diluents, disintegrants, binders, glidants, surfactants, emulsifiers, suspending agents, diluents, and the like, but is not limited thereto.

When the pharmaceutical composition of the present application is prepared in the form of an injection, the ingredients known in the art may be used as pharmaceutically acceptable carriers without limitation as long as they do not interfere with the active expression of the active ingredient.

In particular, the carrier may include, for example, water, saline, aqueous dextrose, pseudo-aqueous, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers, and the like, but is not limited thereto.

The dosage of the pharmaceutical composition of the present application is preferably determined in consideration of the age, sex and condition of the patient, the degree of absorption of the active ingredient in the body, the inactivation rate and the drug used in combination, and may be 0.0001mg/kg body weight to 100mg/kg body weight based on the compound of formula i.

The compound shown in the formula I has remarkable curative effect on various driving mutation lung cancers, and has remarkable curative effect on various non-small cell lung cancers, such as lung adenocarcinoma, lung squamous cell carcinoma or lung large cell carcinoma. The driving mutation is selected from, but not limited to, the following: EGFR mutation, KRAS mutation, HER2 mutation, PIK3CA mutation, BRAF mutation, MET gene mutation or ALK gene rearrangement, ROS1 gene rearrangement, RET gene rearrangement.

The compound shown in the formula I shows remarkable inhibitory activity in an EGFR triple mutant cell KC-1474 subcutaneous transplantation tumor model. The EGFR triple mutant cell KC-1474 is selected from, but not limited to, PC-9EGFR-Del19/T790M/C797S overexpressing cells.

Definition and description

Unless otherwise indicated, the terms and phrases used herein should be construed in a generic sense.

The term "pharmaceutically acceptable" means that the compounds, materials, compositions, and/or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of the compounds of the application prepared from compounds of formula I wherein the compounds are substituted with specific substituents and relatively non-toxic acids or bases.

Drawings

FIG. 1 tumor volume graph for mice of each group

FIG. 2 graph of tumor weight for mice of each group

Detailed Description

Examples in vivo efficacy studies of Compounds of formula I

1 Material

1.1 animals:

female NPG mice, SPF grade, body weight 19-22 g, laboratory animals supplied by Beijing Vetong Biotechnology Co., ltd., laboratory animal production license number SCXK (Beijing) 2019-0002, laboratory animal quality eligibility number: no.110341211100087928.

1.2 major reagents and instrumentation

Reagent name:

RPMI1640, manufacturer: gibco, lot number: 2120614;

FBS, manufacturer: gibco, lot number: 2094468CP;

instrument name:

carbon dioxide incubator, instrument manufacturer: thermo, model: BB15;

ultra clean bench, instrument producer: suzhou Antai air technologies Co., ltd., model: SW-CJ-2FD;

centrifuge, instrument manufacturer: shanghai's pavilion scientific instrument factory, model: TDL-5A;

inverted microscope, instrument manufacturer: OLYMPUS, model: CKX31;

balance, instrument manufacturer: mertrer, model: PL2002;

vernier caliper, instrument manufacturer: SATA, model: world 91512.

2 experimental procedure

2.1 cell culture and seeding

KC-1474 cells used in this experiment were cultured in RPMI1640 medium supplemented with 10% FBS, 0.5. Mu.g/ml puromycin in 5% CO ₂ Is placed in an incubator at 37 ℃. KC-1474 cells were adjusted to a concentration of 1X 10 before cells were continuously cultured for ten passages ⁸ 0.1 mL/mL was inoculated subcutaneously in the right flank of NPG mice, each mouse inoculated with 5X 10 cells, mixed with Matrigel at a volume ratio of 1:1 ⁶ And each.

2.2 grouping and administration

When the average tumor volume of the mice reaches 100-130mm ³ On the left and right, all mice were randomly divided into six groups, model group (V), oral group (po) of compound of formula I, intravenous low dose group (L) of compound of formula I, intravenous medium dose group (M) of compound of formula I, according to tumor volume and body weight. All groups were dosed once daily, starting on the day of grouping and dosing continued for 39 days. The model group was given by intravenous injection with the same volume of vehicle prepared by adding 2g of polyethylene glycol-15 hydroxystearate (HS 15) to 4mL of dimethyl sulfoxide (DMSO), adding 40mL of purified water, and filtering with a 0.22 μm sterilization filter. At the end of the experiment or at the end of the implementation of a humane, animals were euthanized using pentobarbital sodium anesthesia.

The specific grouping and dosing schedule is shown in the following table:

2.3 detection index

2.3.1 tumor volume and tumor volume inhibition (TGI) _TV )

Tumor volume was measured once at the time of grouping, 1 time per week after grouping using vernier calipers, and tumor volume was measured before euthanasia. The tumor volume measurement method comprises the following steps: the long and short diameters of the tumor were measured using vernier calipers.

The calculation formula of the tumor volume is: tumor volume = 0.5 x long diameter x short diameter ² 。

The calculation formula of the tumor volume inhibition rate is as follows: TGI _TV (％)＝[1-(Ti-T0)/(Vi-V0)]×100％

(Ti: mean tumor volume for treatment group at day i of administration, T0: mean tumor volume for treatment group at day 0 of administration; vi: mean tumor volume for model group at day i of administration, V0: mean tumor volume for model group at day 0 of administration).

2.3.2 tumor weight and tumor weight inhibition (TGI) _TW )

At the end of the experiment, tumor tissues were removed after euthanasia of the animals, the tumor weights were weighed, and the tumor weight inhibition rate was calculated as follows:

TGI _TW (％)＝(W _{model group} -W _{Treatment group} )/W _{Model group} X 100%, W refers to tumor weight.

3. Results and conclusions

Analysis was performed based on the raw data, and the analysis of the results was expressed in Mean ± SD. At the same time, statistical analysis was performed on tumor volume and tumor weight, with P <0.05 considered significant differences.

All animals were well active and fed during dosing and observation. As shown in FIG. 1, at the end of the experiment, the average tumor volume of the mice in the model group was 1082.+ -.225 mm ³ Tumor volume inhibition rates of po group L, M groups were 28%, 31%, 57%, respectively; as shown in FIG. 2, the average tumor weight of the mice in the model group was 1.1792.+ -. 0.0989g, and the tumor weight inhibition ratios in the po group L, M group were 21%, 22% and 61%, respectively.

In summary, in the mouse KC-1474 cell subcutaneous transplantation tumor model, po group L, M has an inhibitory effect on tumor growth compared to the model group, wherein the difference between M group and model group is extremely significant (P < 0.001), and po group L, M has an effect of reducing tumor volume, showing good anti-tumor efficacy.

Claims (10)

1. Use of a compound of formula i or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer, the compound of formula i having the formula:

2. the use according to claim 1, wherein the cancer is selected from lung cancer, head and neck cancer, breast cancer, prostate cancer, esophageal cancer, rectal cancer, colon cancer, nasopharyngeal cancer, uterine cancer, pancreatic cancer, lymphoma, leukemia, osteosarcoma, melanoma, glioma, renal cancer, gastric cancer, liver cancer, bladder cancer, skin cancer, thyroid cancer or colorectal cancer.

3. The use according to claim 2, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

4. The use of claim 3, wherein the non-small cell lung cancer is selected from lung adenocarcinoma, lung squamous cell carcinoma or lung large cell carcinoma.

5. The use of claim 4, wherein the non-small cell lung cancer is lung adenocarcinoma.

6. The use of claim 2, wherein the lung cancer is selected from EGFR-mutated lung cancer, KRAS-mutated lung cancer, HER 2-mutated lung cancer, PIK3 CA-mutated lung cancer, BRAF-mutated lung cancer, MET-gene-mutated lung cancer or ALK-gene-rearranged lung cancer, ROS 1-gene-rearranged lung cancer, RET-gene-rearranged lung cancer.

7. The use of claim 6, wherein the EGFR-mutant lung cancer is selected from the group consisting of EGFR-Del19 mutant lung cancer, EGFR-L858R mutant lung cancer, EGFR-C797S/T790M mutant lung cancer, EGFR-L858R/T790M mutant lung cancer, EGFR-Del19/T790M mutant lung cancer, EGFR-L858R/T790M/C797S mutant lung cancer, and EGFR-Del19/T790M/C797S mutant lung cancer.

8. The use of claim 7, wherein the EGFR-mutated lung cancer non-small cell lung cancer is egfrde 19/T790M/C797S mutated lung adenocarcinoma.

9. A pharmaceutical composition for treating lung cancer, which comprises a compound represented by formula i or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

10. The use according to claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is formulated into an oral dosage form or a parenteral dosage form, the oral dosage form being a tablet, pill, granule, powder, capsule, syrup, emulsion, microemulsion; the parenteral dosage form is an injection.