CN115040519A - Use of EGFR inhibitors for the treatment of rare or non-classical mutations - Google Patents

Use of EGFR inhibitors for the treatment of rare or non-classical mutations Download PDF

Info

Publication number
CN115040519A
CN115040519A CN202210220022.3A CN202210220022A CN115040519A CN 115040519 A CN115040519 A CN 115040519A CN 202210220022 A CN202210220022 A CN 202210220022A CN 115040519 A CN115040519 A CN 115040519A
Authority
CN
China
Prior art keywords
cancer
formula
egfr
compound
tumor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202210220022.3A
Other languages
Chinese (zh)
Inventor
王婷
张晓婷
张福军
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Original Assignee
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
Publication of CN115040519A publication Critical patent/CN115040519A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The present invention relates to the use of an EGFR inhibitor for the treatment of non-rare or non-classical mutations. The invention relates to a compound with a structure shown in a formula (I) and a formula (II) and application of a metabolite thereof as an EGFR inhibitor. In particular, the invention relates to compounds shown as a formula (I) and a formula (II), which have the activity of inhibiting EGFR mutations such as EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and exon20 insertion and the like, can be used for treating diseases mediated by the activity of the EGFR mutants alone or partially, and have wide application in preventing and treating cancers, particularly in treating non-small cell lung cancer.

Description

Use of EGFR inhibitors for the treatment of non-rare or non-classical mutations
Technical Field
The invention belongs to the field of pharmaceutical medicine, and particularly relates to an Epidermal Growth Factor Receptor (EGFR) inhibitor compound shown in formula (I) and/or (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and application of the compound in preparation of medicines for treating tumors or cancers with one or more EGFR mutations.
Background
Egfr (epidemal Growth Factor receptor) is a member of the ErbB family of transmembrane receptor tyrosine kinases and is activated by binding to its ligand Epidermal Growth Factor (EGF) or transforming Growth Factor alpha (TGF α). Activated EGFR forms homodimers on cell membranes or heterodimers with other receptors in the family (e.g., ErbB-2, ErbB-3, or ErbB-4), causing phosphorylation of key tyrosine residues in EGFR cells, thereby activating downstream signaling pathways in the cell, which play an important role in cell proliferation, survival, and anti-apoptosis. Activating mutation, overexpression, gene amplification and the like of the EGFR can cause over-activation of the EGFR, promote transformation of cells into tumor cells, play an important role in proliferation, invasion, metastasis and angiogenesis of the tumor cells, and are important targets for development of anti-cancer drugs, particularly lung cancer treatment drugs.
First generation EGFR small molecule inhibitors including gefitinib (iressa) and erlotinib (tarceva) showed good efficacy in lung cancer treatment, and have been used as first line drugs for the treatment of non-small cell lung cancer (NSCLC) with EGFR activating mutations including L858R and deee 746_ a 750. However, after 10-12 months of treatment with the first-generation small molecule EGFR inhibitor, almost all NSCLC patients develop drug resistance to the first-generation small molecule inhibitor, and more than half of the drug resistance mechanism is caused by secondary mutation of the EGFR gatekeeper gene residue T790M.
Amatinib (Almonertib) is a third-generation EGFR TKI inhibitor, has high response rate and good treatment effect on drug resistance caused by EGFR T790M mutation, is approved by the Chinese national drug administration to be marketed in 3 months in 2020, and can be used for clinically and effectively treating patients with advanced non-small cell lung cancer with EGFR T790M drug resistance mutation. Currently, the main application of the amatinib is to treat first-line and second-line non-small cell lung cancer of EGFR activating mutation (comprising L858R and deee 746_ A750) and drug-resistant mutation EGFR T790M, and EGFR mutations such as EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and Exon20 insert account for a certain proportion of lung cancer, so that the research and development of inhibitors against these very common mutations also have important clinical application value.
Lung cancer is a serious disease threatening human health, and the death rate of lung cancer accounts for the first place of all malignant tumors. In China, the incidence of lung cancer is increasing year by year, and about 70 ten thousand new cases are sent every year. The cases of lung cancer accompanied by EGFR activation or drug resistance unusual/non-classical mutation in China account for about 10% of all EGFR mutations, and the medication of the patients is not clearly guided at present, so that the research and development of inhibitors for EGFR unusual mutation have important clinical and market values.
Disclosure of Invention
The invention aims to provide a compound shown in a formula (I) or (II), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound shown in the formula (I) or (II) has the following structure:
Figure BDA0003536822060000021
the compound of formula (I) and/or (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is used in the medicine for treating tumors or cancers. Wherein the tumor or cancer has one or more EGFR mutations; preferably with point mutations, insertions and/or deletions of 1 to 18 nucleotides at exons 18, 19, 20 or 21; more preferably a mutation having insertion of EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and exon 20.
In a preferred embodiment of the invention, the pharmaceutically acceptable salt of the compound may be hydrochloride, phosphate, hydrogen phosphate, sulfate, hydrogen sulfate, 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.
In a preferred embodiment of the invention, the compound of formula (I) and/or (II) is a mesylate salt thereof.
In a preferred embodiment of the invention, the tumor or cancer is bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, membrane adenocarcinoma, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, leukemia or multiple myeloma or lymphoma, preferably lung cancer, more preferably non-small cell lung cancer.
In a preferred embodiment of the invention, the exon20 insertion mutations include, but are not limited to, V769-D770 InsASV, D770-N771 InsSVD, H773-V774 insX, P772-H773 insX, N771-P772 insX, A763-Y764 insX, V774-C775 insX, S768-V769 InsX.
In a preferred embodiment of the invention, the tumor or cancer is lung cancer mutated in one or more of EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and exon20 insertion.
In a preferred embodiment of the invention, the tumor or cancer is one or more of mutant non-small cell lung cancers of EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and exon20 insertion.
In a preferred embodiment of the invention, the EGFR inhibitor is administered in a single dose selected from the range of 1 to 1000mg, and the dose may be administered once a day, twice a day, or three times a day. Exemplary dosages, based on the free base, are selected from 1mg, 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg, 27.5mg, 30mg, 32.5mg, 35mg, 37.5mg, 40mg, 42.5mg, 45mg, 47.5mg, 50mg, 52.5mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 165mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 950mg, 750mg, or 1000 mg.
In a more preferred embodiment of the invention, the compound of formula (I) and/or (II) is administered in a daily dose of 55mg or 110 mg.
In a more preferred embodiment of the invention, the compounds of formula (I) and/or (II) are administered once a day, twice a day or three times a day, preferably once a day.
In a further preferred embodiment of the invention, the compound of formula (I) and/or (II) is administered in a daily dose of 165mg, once a day.
In a further preferred embodiment of the invention, in said use or method, the compound of formula (I) and/or formula (II) has a tumor-inhibiting effect on Ba/F3(EGFR L861Q) non-classical mutations, the inhibition being dose-dependent.
The invention also provides an application of the compound shown in the formula (I) and/or (II), the stereoisomer thereof or the pharmaceutically acceptable salt thereof in preparing a medicament for treating tumors or cancers, which is characterized in that:
the tumor or cancer is a non-small cell lung cancer having one or more EGFR mutations;
the EGFR mutation is selected from one or more of L861Q, G719X or S768I mutations;
the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer; further, locally advanced or metastatic non-small cell lung cancer is the non-small cell lung cancer of IIIB, IIIC or IV stage which recurs or is initially diagnosed after the previous operation treatment;
Figure BDA0003536822060000031
in a further preferred embodiment of the present invention, the compound of formula (I) and/or (II) is administered in a daily dose of 165 mg;
the compound of formula (I) and/or (II) is administered once daily; and is
Can be continuously used.
In another aspect, the present invention provides a pharmaceutical composition of a compound of formula (I) or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients. The pharmaceutical composition is used for treating tumors or cancers, wherein the tumors or cancers have one or more EGFR mutations; preferably with point mutations, insertions and/or deletions of 1 to 18 nucleotides at exons 18, 19, 20 or 21; more preferably a mutation having insertion of EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and exon 20.
In a preferred embodiment of the invention, the medicament prepared from a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is suitable for oral administration.
In a preferred embodiment of the invention, the compounds of formula (I) or (II) can also be used in combination with other tumor therapeutic agents.
The term "combination" as used herein is intended to mean a mode of administration in which at least one dose of a chemotherapeutic agent and at least one dose of an EGFR inhibitor are administered over a period of time, wherein both substances exhibit pharmacological effects. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. The chemotherapeutic agent and the EGFR inhibitor may be administered simultaneously or sequentially. Such terms include treatments wherein the chemotherapeutic agent and the EGFR inhibitor are administered by the same route of administration or different routes of administration.
In a preferred embodiment of the invention, the compound of formula (I) and/or (II) may be administered once a day, twice a day, three times a day; the frequency of administration of the chemotherapeutic agent may be once a week, twice a week, once every two weeks, once every three weeks.
The term "effective amount" refers to an amount of a drug effective to treat a disease or disorder in a mammal. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the size of the tumor; inhibit (i.e., slow to some extent and preferably prevent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably prevent) tumor metastasis; inhibit tumor growth to some extent; and/or to alleviate one or more symptoms associated with the condition to some extent. Depending on the extent to which the drug can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic. For cancer treatment, in vivo efficacy can be measured by assessing survival duration, Progression Free Survival (PFS) duration, Response Rate (RR), response duration, and/or quality of life.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Drawings
FIG. 1 therapeutic effect of drug A on Ba/F3(EGFR L861Q) transplantable tumors;
FIG. 2 weight effect of drug A on Ba/F3(EGFR L861Q) tumor-bearing mice.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Example (b): biological assay
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 assay for inhibition of EGFR unusual/atypical mutase Activity by Compounds of the present invention
Purpose of the experiment: the purpose of this test example was to test the in vitro inhibitory activity of the mesylate salts of compounds (I) and (II) against 7 EGFR uncommon/atypical mutant enzymes.
Main reagent materials:
TABLE 1 Experimental reagent materials information
Figure BDA0003536822060000051
Figure BDA0003536822060000061
An experimental instrument:
TABLE 2 Experimental instrumentation information
Figure BDA0003536822060000062
The experimental method comprises the following steps:
the inhibitory activity of the compounds on EGFR non-common/non-classical mutant enzymes was detected by Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET). The highest concentration of compounds of formula I and formula II detected in EGFR D761Y, L747S, L861Q and D770_ N771 insNPG mutase was 1 μ M, 3-fold dilution, total 11 concentrations; the highest concentration tested in EGFR G719C, G719D, G719S mutant enzymes was 10 μ M, 3-fold dilution, for a total of 11 concentrations. 1 Xkinase buffer (50mM HEPES, 1mM EGTA, 10mM MgCl) was prepared 2 2mM DTT, 0.01% Tween-20), 4 XCompound solution, 4 Xenzyme solution and 2 XULight-poly GT/ATP substrate solution were prepared using 1 Xkinase buffer. Add 2.5. mu.L of 4 Xenzyme solution and 2.5. mu.L of 4 XCompound solution to 384 well plates, pre-incubate for 10 min at room temperature, add 5. mu.L of 2 XULight-poly GT/ATP substrate solution to a final DMSO concentration in the whole plate of 0.2%, incubate for 45 min at room temperature, add 10. mu.L EDTA and
Figure BDA0003536822060000063
and detecting the mixed solution by using Eu-W1024 Anti-phosphotyrosine (PT66), incubating for 1 hour at room temperature, and measuring the 665nm fluorescence signal value of each plate hole by using a microplate reader.
The specific experimental operations were as follows:
kinase enzymesThe reaction was performed in white 384-well plates (Perkin Elmer #6007290) with 2.5. mu.L of ddH containing 0.5-1% DMSO per well 2 O diluted compounds of different concentrations, positive control wells added 2.5. mu.L ddH containing 0.5-1% DMSO 2 O, centrifuge at 1000rpm for 1 minute. Then 2.5. mu.L of Dilution buffer (1 Xkinase buffer, 50mM HEPES, 1mM EGTA, 10mM MgCl) was added to each well 2 2mM DTT, 0.01% Tween-20) diluted 0.01-1 nM 4 × EGFR D761Y, L747S, L861Q, G719C, G719D, G719S, D770_ N771 insNPG in kinase solution, 2.5 μ L Dilution buffer was added to the negative control wells, centrifugation was carried out at 1000rpm for 1 minute, the plates were closed, and the compound was incubated with the enzyme at room temperature for 10 minutes. mu.L of 2 XU-Light-PolyGT (25nM)/ATP (40. mu.M) substrate mix was added to all wells, centrifuged at 1000rpm for 1 min, sealed and reacted at room temperature for 45 min. Finally, 10. mu.L of the mixture was added
Figure BDA0003536822060000073
Detecting a mixed solution (Eu-labelled Anti-phosphotyrisine (PT 66)) by using Eu-W1024 Anti-phosphotyrisine (PT66), centrifuging at 1000rpm for 1 minute, sealing a plate, reacting at room temperature for 1 hour, reading the plate by using a time-resolved fluorescence program on a microplate reader, and detecting a fluorescence value at a 665nM emission wavelength.
The experimental data processing method comprises the following steps:
1) the inhibition was calculated using the fluorescence signal value at 665 nm.
Figure BDA0003536822060000071
The positive control wells are non-compound enzyme reaction wells, and the negative control wells are non-enzyme reaction wells.
2) Concentrations and inhibition were fitted using log (inhibitor) vs. response- -Variable slope (four parameters) in GraphPad prism6.0 to yield IC 50 The value, the equation is calculated as Y ═ Bottom + (Top-Bottom)/(1+10^ ((LogIC50-X) · HillSlope)).
TABLE 3 in vitro inhibitory Activity IC on EGFR non-common/non-classical mutant enzymes 50 Summary of the invention
Figure BDA0003536822060000072
And (4) conclusion:
the compound of formula (I) has obvious inhibition effect on enzyme activities of EGFR D761Y, L747S, L861Q and D770_ N771 insNPG, and IC 50 Respectively at 0.84nM, 3.09nM, 1.07nM and 0.4nM, and has strong inhibitory effect on EGFR G719C, G719D and G719S enzyme activity, IC 50 The inhibitory activity of the compound of formula (II) on 6 EGFR non-common/non-classical mutant kinases was comparable to that of the compound of formula (I) at 17.25nM, 54.14nM, 82.80nM, respectively.
Test example 2 assay for inhibition of EGFR unusual/atypical mutant cell Activity by Compounds of the present invention
Purpose of the experiment: the purpose of this test example was to test the in vitro inhibitory activity of the mesylate salt of compounds (I) and (II) against 6 EGFR uncommon/atypical mutant cells.
Main reagent materials:
cell line (b):
cell lines Cell type Cell number/well Culture medium
Ba/F3 EGFR S768I Suspended in water 3000 RPMI-1640+10％FBS
Ba/F3 EGFR G719S Suspended in water 3000 RPMI-1640+10％FBS
Ba/F3 EGFRG719S/T263P Suspended in water 3000 RPMI-1640+10％FBS
Ba/F3 EGFR L861Q Suspension (suspension) 3000 RPMI-1640+10％FBS
Ba/F3 EGFR T790M/L861Q Suspension (suspension) 3000 RPMI-1640+10％FBS
Ba/F3 EGFR-D770-N771ins_SVD Suspended in water 3000 RPMI-1640+10％FBS
Reagent and consumable
Figure BDA0003536822060000081
The instrument comprises the following steps:
Figure BDA0003536822060000082
the experimental method comprises the following steps:
culturing the non-common/non-classical mutant Ba/F3 cells to appropriate density, collecting the cells, adjusting the cells to appropriate cell concentration using complete medium, spreading the cell suspension in 96-well plate at 90. mu.L/well, placing at 37 ℃ and 5% CO 2 Adhering the incubator to the wall overnight, preparing compound solutions with different concentrations by using DMSO and a culture medium, setting a solvent control, adding the compound solutions into a 96-well plate, placing 10 mu L of each well, placing at 37 ℃ and 5% CO 2 After the culture in the incubator is continued for 72h, CellTiter-Glo solution is added, after uniform shaking and mixing, the mixture is incubated for 10 to 20 minutes in the dark, and the reading is carried out by a microplate reader.
The experimental data processing method comprises the following steps:
calculating the inhibition rate by using the luminescence signal value, and fitting the concentration and the inhibition rate by using Graphpad Prism software to obtain IC 50 The value is obtained.
TABLE 4 in vitro inhibitory Activity IC on EGFR non-common/non-classical mutant enzymes 50 To summarize
Figure BDA0003536822060000091
And (4) conclusion:
the compounds of formula (I) and (II) mesylate have significant in vitro inhibitory activity against EGFR non-common/non-classical mutant cells.
Test example 3, in vivo pharmacodynamic evaluation of drug a in the Ba/F3(EGFR L861Q) cell line nude mouse subcutaneous graft tumor model
1. Experimental Material
Drug A the mesylate of the compound of formula (I) according to the invention was prepared according to the method disclosed in WO2016054987 using a pH4.18 acetate buffer for the pharmaceutical preparation.
Ba/F3(EGFR L861Q) engineered cells were purchased from Congyaobo, and maintained by Shanghai Hansen Bio-medical technology, Inc. for species conservation and subculture. The cell is cultured in vitro in suspension culture in RPMI1640 culture medium supplemented with 10% fetal calf serum, 100U/mL penicillin and 100. mu.g/mL streptomycin at 37 deg.C in 5% CO2 cell incubator. Routine treatment passages were performed three times a week. When the cell number reaches the requirement, collecting the cells, counting and inoculating.
Nude mice, 6-8 weeks female, purchased from Shanghai Sphere-BikKa laboratory animals Co., Ltd, housed in constant temperature, constant humidity, and independent ventilated boxes in SPF-level animal houses.
2. Experimental methods
Culturing Ba/F3(EGFR L861Q) cells in vitro, expanding the number of cells to the number required for in vivo inoculation and reaching 2-4X 10 in culture flask 6 At/ml density, cells were harvested by centrifugation. Ba/F3(EGFR L861Q) cells (2X 10) 6 /one) was inoculated subcutaneously into the right front back of each mouse until the tumor grew to an average volume of 100mm 3 Thereafter, the animals were randomly assigned (D0). Mice were gavaged once daily (QD) at a dose volume of 10mL/kg, and the solvent group was given the same volume of "solvent" (pH 4.18 acetate buffer); specific dosages and schedules are shown in table 5. Tumor volume was measured, mouse body weight was weighed and data was recorded.
The experimental index is to examine the influence of the drug on the tumor growth, and the specific index is T/C% or tumor inhibition rate TGI (%).
The tumor diameter is measured by a vernier caliper, and the tumor volume (V) is calculated by the formula:
V＝1/2×a×b 2 wherein a and b represent length and width, respectively.
T/C(％)＝(T-T 0 )/(C-C 0 ) X 100 wherein: t, C is the tumor volume at the end of the experiment, T 0 、C 0 Tumor volume at the beginning of the experiment.
Tumor inhibition rate (TGI) (%) 100-T/C (%).
When tumors regress, tumor inhibition rate (TGI) (%) 100- (T-T) 0 )/T 0 ×100
If the tumor is reduced from the initial volume, i.e. T<T 0 Or C<C 0 When, it is defined as partial tumor regression (PR); if the tumor completely disappears, it is defined as complete tumor regression (CR).
The experiment is finished, the experimental end point is reached, or the tumor volume reaches 2000mm 3 ，CO 2 The sacrifice was anesthetized.
The experimental data were analyzed and plotted using GraphPad Prism 9.0. Three or more groups were compared using one-way ANOVA reproduced measures, and if there were significant differences in F-values, multiple comparisons should be made using Dunnett's after ANOVA analysis. P <0.05 was defined as statistically significant.
TABLE 5 dosing regimen
Figure BDA0003536822060000101
3. Results of the experiment
The growth inhibitory effect of drug A on the Ba/F3(EGFR L861Q) model is shown in Table 6, and the body weight change of each group of animals in the Ba/F3(EGFRL861Q) model is shown in Table 7.
TABLE 6 growth inhibition of Ba/F3(EGFR L861Q) model by drug A
Figure BDA0003536822060000102
Note: p value D14: dunnett's analysis was performed using one-way ANOVA as a control based on tumor volume of each animal in the different groups;
TABLE 7 weight changes in the Ba/F3(EGFR L861Q) model for each group of animals
Figure BDA0003536822060000111
Note:
a, calculating the experiment time: the day of grouping (day0), the day of dosing (D1) started the calculation;
data expressed as "mean. + -. standard error
At the end of the experiment, the mean tumor volumes of drug A10 mg/kg, 20mg/kg and 40mg/kg were 1029mm 3 、581mm 3 、148mm 3 The tumor inhibition rates are respectively 2%, 49% and 95%, compared with the solvent group, the medium-dose group and the high-dose group have significant statistical difference, and 4/10 animals in the high-dose group have partial tumor regression. The whole experiment has been carried outIn the course, 1 animal died in day11 and day14 in the solvent group and the low dose group, respectively, no animal died in the medium dose group and the high dose group, the animal died independent of the drug, and the tumor-bearing mice were well tolerated by the compound dose. The curative effect of the medicine A on Ba/F3(EGFR L861Q) transplanted tumor is shown in figure 1. The effect of drug A on body weight of Ba/F3(EGFR L861Q) bearing mice is shown in FIG. 2.
4. Conclusion of the experiment
The drug A has tumor inhibition effect on the non-classical mutation of Ba/F3(EGFR L861Q), the inhibition effect is dose-dependent, and no obvious toxic or side effect is shown.

Claims (10)

1. Use of a compound of formula (I) and/or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a tumor or cancer having one or more EGFR mutations; preferably with point mutations, insertions and/or deletions of 1 to 18 nucleotides at exons 18, 19, 20 or 21; more preferably a mutation having insertion of EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and exon 20;
Figure FDA0003536822050000011
2. use according to claim 1, characterized in that the compound of formula (I) and/or (II) is a mesylate salt thereof.
3. The use according to claim 1, wherein the tumor or cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, esophageal cancer, gallbladder cancer, ovarian cancer, membrane adenocarcinoma, stomach cancer, cervical cancer, thyroid cancer, prostate cancer, skin cancer, leukemia, and multiple myeloma or lymphoma; preferably lung cancer; non-small cell lung cancer is more preferred.
4. The use of claim 1, wherein the exon20 insertion mutation comprises V769-D770 InsASV, D770-N771 InsSVD, H773-V774 insX, P772-H773 insX, N771-P772 insX, a763-Y764 insX, V774-C775 insX, S768-V769 insX.
5. The use of claim 1, wherein the tumor or cancer is lung cancer having one or more mutations in EGFR L861Q, D761Y, L747S, S768I, G719C, G719D, G719S and exon20 insertions; non-small cell lung cancer is preferred.
6. Use according to claim 1, wherein the compound of formula (I) and/or (II) is administered in a daily dose of 1-1000 mg; preferably 10-200 mg; more preferably 55mg, 110mg or 165 mg; the compounds of formula (I) and/or (II) are administered once a day, twice a day or three times a day, preferably once a day.
7. Use according to claim 6, wherein the compound of formula (I) and/or (II) is administered in a daily dose of 165 mg; the compounds of formula (I) and/or (II) are administered once daily.
8. The use of a compound of formula (I) and/or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, for the preparation of a medicament for the treatment of a tumor or cancer, wherein:
the tumor or cancer is a non-small cell lung cancer having one or more EGFR mutations;
the EGFR mutation is selected from one or more of L861Q, G719X or S768I mutations;
the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer; further, locally advanced or metastatic non-small cell lung cancer is stage IIIB, IIIC or IV non-small cell lung cancer which has relapsed or is initially diagnosed after the previous surgical treatment;
Figure FDA0003536822050000021
9. use of a compound of formula (I) and/or (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 8, in the manufacture of a medicament for the treatment of a tumor or cancer, further characterized in that:
the compound of formula (I) and/or (II) is administered in a daily dose of 165 mg;
the compound of formula (I) and/or (II) is administered once daily; and is
Can be administered continuously.
10. A pharmaceutical composition comprising a compound of formula (I) and/or (II) as claimed in any one of claims 1 to 9, in association with one or more pharmaceutically acceptable excipients, diluents or carriers.
CN202210220022.3A 2021-03-08 2022-03-08 Use of EGFR inhibitors for the treatment of rare or non-classical mutations Pending CN115040519A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2021102519164 2021-03-08
CN202110251916 2021-03-08

Publications (1)

Publication Number Publication Date
CN115040519A true CN115040519A (en) 2022-09-13

Family

ID=83158335

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210220022.3A Pending CN115040519A (en) 2021-03-08 2022-03-08 Use of EGFR inhibitors for the treatment of rare or non-classical mutations

Country Status (1)

Country Link
CN (1) CN115040519A (en)

Similar Documents

Publication Publication Date Title
US11291667B2 (en) Combination therapy involving diaryl macrocyclic compounds
US20180325901A1 (en) Chiral diaryl macrocycles and uses thereof
US11666574B2 (en) Combination therapy involving diaryl macrocyclic compounds
TWI762784B (en) Use of cdk4/6 inhibitor in combination with egfr inhibitor for preparation of medicament for treating tumor diseases
CN110652514A (en) Pharmaceutical use of third generation EGFR inhibitor
WO2022042755A1 (en) Compound for inhibiting mutant egfr and use thereof
CN111712245A (en) Therapeutic agent for hepatocellular carcinoma
US10039764B2 (en) Treatment and diagnosis of cancer and precancerous conditions using PDE10A inhibitors and methods to measure PDE10A expression
KR20120099219A (en) Combination
CN115040519A (en) Use of EGFR inhibitors for the treatment of rare or non-classical mutations
CA2576926C (en) Use of midostaurin for treating gastrointestinal stromal tumors
JP2013505962A (en) combination
CN117679421A (en) Application of pyrido [1,2-a ] pyrimidinone compound
WO2021061695A1 (en) Treatment of egfr mutant-related cancers using a combination of egfr and cdk4/6 inhibitors
CN114641293A (en) Application of FGFR inhibitor
KR101739158B1 (en) Combination
CN114948964B (en) Use of multi-target protein kinase inhibitors
CN110623952B (en) Application of indole compounds in preparation of medicines for treating myeloproliferative tumors
CN115006397A (en) Pharmaceutical application for preventing or treating tumor diseases
RU2784853C2 (en) Combination therapy using diaryl macrocyclic compounds
JP7093764B2 (en) How to treat myelodysplastic syndrome
Feng et al. NEP010, a novel compound with minor structural modification from afatinib, exhibited significantly improved antitumor activity
WO2024097848A1 (en) Malonate and glycolate salts of an egfr inhibitor
WO2024054898A1 (en) Onvansertib and parp inhibitor combination
CN115887473A (en) Application of verbascoside compound or derivative thereof in preparation of bladder cancer resistant medicines

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination