CN115607551A - Novel use of EGFR inhibitor - Google Patents

Novel use of EGFR inhibitor Download PDF

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Publication number
CN115607551A
CN115607551A CN202110803492.8A CN202110803492A CN115607551A CN 115607551 A CN115607551 A CN 115607551A CN 202110803492 A CN202110803492 A CN 202110803492A CN 115607551 A CN115607551 A CN 115607551A
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mutation
egfr
phenyl
cancer
20insx
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李文华
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Shanghai Huilun Pharmaceutical Co ltd
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Shanghai Huilun Pharmaceutical Co ltd
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Priority to PCT/CN2022/105243 priority patent/WO2023284747A1/en
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems

Abstract

The invention discloses a new application of an EGFR inhibitor, wherein the EGFR inhibitor is N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide, and the compound can be used for preparing a medicament for treating diseases containing EGFR 20insX mutation, EGFR G719X mutation and ERBB2 mutation.

Description

Novel use of EGFR inhibitor
Technical Field
The invention relates to the field of drug therapy, and in particular relates to application of N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide in preparation of a drug for treating diseases.
Background
According to the prior literature, 93% of EGFR mutations appear in exons 18-21, more than 80% are Del19 and L858R, and the rest are rare mutations, including G719X, E709X on exon 18, ins19 on Del18, 19 exon, ins20 on exon 20, L861Q on exon 21, and the like.
Common EGFR mutation inhibitors (EGFR TKIs) include first generation gefitinib, erlotinib, second generation afatinib, dacatinib, third generation axitinib (Osimertinib), and the like. EGFR TKI significantly prolonged progression-free survival and overall survival in EGFR mutant patients. Particularly, the third-generation drug oseltamiib can inhibit the EGFR T790M mutation with acquired drug resistance.
The EGFR 20ins mutation is a collective term for a collection of mutations, clustered at exons 18-22, which encode the tyrosine kinase domain. In particular, it is within about 15 amino acids (D761-C775) of exon 20. It has now been found that 122 EGFR 20ins mutations, mostly occur in Met766-Cys775 following the C helix, and a few in G1u762-Tyr764 located in the C helix. Of these 20.5% of the insertional mutations started at Va1769, 28.7% at Asp770, 17.2% at Pro772 and 14% at His773. The most common mutations are A770-A771insX followed by V769-A770insX, H773-V7741ins X, P772-H773ins, etc.
The first generation EGFR inhibitor has good inhibitory activity to A763-Y764insFQEA mutation, and has a treatment effect as high as 72% of RR and PFS in nearly 10 months. Second generation EGFR and third generation EGFR inhibitors have good inhibitory activity against specific EGFR 20 ins. Pocitinib was able to target the Ins20 mutations of EGFR and HER2, with mPFS for both Ins20 mutations at 5.5 months and 5.1 months, respectively.
It has been reported in the literature that EGFR mutations are found in squamous cell carcinoma of sinus (SNSCC) at a very high frequency (77% of SNSCC tumors), mainly EGFR 20ins mutations, indicating that EGFR 20ins mutations are not completely localized to lung cancer.
Disclosure of Invention
The invention provides application of a compound N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide (compound A) or pharmaceutically acceptable salt thereof in preparing a medicament for treating diseases, wherein the diseases contain at least one EGFR 20insX mutation, EGFR G719X mutation and ERBB2 mutation.
In a further aspect of the invention, the invention provides an application of a compound N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide in preparing a medicament for treating EGFR 20insX mutation diseases, wherein the EGFR 20insX mutation is EGFR V774-C775insX mutation, EGFR H773-V774insX mutation, EGFR P772-H773insX mutation, EGFR N771-P772insX mutation, EGFR D770-N771insX mutation, EGFR V769-D770insX mutation, EGFR S768-V769insX mutation, EGFR A767-S768insX mutation, EGFR V-M766 insX mutation, EGFR Y764-V76X mutation, EGFR A3-Y764 insX mutation, and EGFR D761-E762X mutation.
In a further aspect of the invention, the invention provides application of a compound N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide in preparation of a medicament for treating EGFR 20insX mutation diseases, wherein the EGFR 20insX mutation is preferably EGFR V774-C775insX mutation, EGFR H773-V774insX mutation, EGFR P772-H773insX mutation, EGFR N771-P772insX mutation, EGFR D770-N771insX mutation and EGFR V769-D770insX mutation.
In a further aspect of the invention, the invention provides a use of a compound N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide in the preparation of a medicament for treating EGFR 20ins mutation diseases, wherein the EGFR 20ins X mutation is preferably EGFR H773-V774ins X mutation, EGFR D770-N771ins X mutation, or EGFR V769-D770ins X mutation.
The X represents amino acid, and the amino acid is G, A, V, L, I, P, F, Y, W, S, T, C, M, N, Q, D, E, K, R and H; in a preferred embodiment of the present invention, X is any one of amino acids, or any combination of two or more thereof, or any combination of three or more thereof, or any combination of four or more thereof. The specific embodiment of the invention comprises the following steps: v769_ D770insASV, D770_ N771insSVD, A763_ Y764insFQEA, A763_ Y764insLQEA, Y764_ V765insHH, M766_ A767insASV, A767_ S768insASVD, S768_ V769insIL, S768_ V769insPL, S768_ V769insTLASV, S768_ DV769insLDS, S768_ D770dupSVD, V769_ D770insSAVS, V769_ D770insSGSV, V769_ D770insSLRD, V769_ D770 DNinsDNinsP, V769_ D770insGTM, V769_ D770insGTR, V769_ D770insGVM, V769_ D770insE, V769_ D770insGTV, V769_ H773 insLDNPH, D770_ N771insG, D770_ N771insY, D770_ N771insH, D770_ N771insNPY, D770_ N771insGYN, D770_ N771insGSVDN, D770_ N771 insGVDN, D770_ N771insQVH, D770_ N771insAVD, D770_ N771insGT, D770_ N771 GV, D770_ N insNPG, D770_ N771 egN, N771_ P insKFP, N771_ P772insKGP, N771_ P772insRDP, N771_ P772insSEDNS, N771_ P772insSHP, N771_ P772insSPHP, N771_ P772insSVDSP, N771_ P772insGTDN, N771_ P772insGYP, N771_ P772 NN, N771_ P772insV, N771_ P772insY, N771_ P772G, N771_ P772H, N771_ P772insT, N771_ P772insHH, P772H 773insGT, P773 insDNP, P772H 773insDNP, P772_ H773insRVDNP, P772_ H773insPHP, P772_ H773insNPNP, H773_ V774insAH, H773_ V774insTH, H773_ V774insSH, H773_ V774insP, H773_ V774insPNPYV, H773_ V774 insNPYV, H773_ V774insHPH, H773_ V774insPY, H773_ V774insNPY, V774 insAHVC, V774_ C775 insGNVC, V _ C775 insGTNPC.
As a preferred embodiment of the invention, the EGFR 20insX mutation is optionally selected from: at least one of EGFR V769_ D770insASV mutation, EGFR V769_ D770insDNP mutation, EGFR D770_ N771insNPG mutation, EGFR D770_ N771insG mutation, EGFR D770_ N771insNPH mutation, EGFR D770_ N771insSVD mutation, EGFR H773_ V774insPH mutation and EGFR H773_ V774insH mutation.
In a further aspect of the invention, there is provided a use of the compound N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide in the manufacture of a medicament for the treatment of a disease mediated by the G719X mutation of EGFR, amino acid X being a, S, D, C, specifically including: at least one of an EGFR G719A mutation, an EGFR G719S mutation, an EGFR G719D mutation, and an EGFR G719C mutation.
In a further aspect of the invention there is provided the use of the compound N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide in the manufacture of a medicament for the treatment of diseases mediated by ERBB2 (also known as HER 2) mutations, the ERBB2 mutations comprising: at least one of an ERBB 2D 769Y mutation, an ERBB 2V 777_ G778insCG mutation, an ERBB 2V 777L mutation, an ERBB 2A 775_ G776insYVMA mutation; the ERBB 2A 775_ G776insYVMA mutation is preferred.
In a further aspect, the present invention provides the use of N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, optionally containing an EGFR L861Q mutation, an EGFR S768I mutation.
In a further aspect of the invention, there is provided a use of the compound N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease, which is cancer, as a preferred embodiment of the invention. Such cancers include, but are not limited to, lung, breast, pancreatic, prostate, ovarian, and the like.
Detailed Description
Reference is made to the processes disclosed in CN106279173A, and also in CN103930425A for the preparation of the compounds according to the invention.
Example 1
Kinase profiling screening reactions: basic buffer solution: 20mM Hepes (pH 7.5), 10mM MgCl 2 ,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na 3 VO 4 2mM DTT,1% DMSO. The required coenzyme factors are added separately to each kinase reaction. Compound treatment: the compounds of the present invention were dissolved in 100% DMSO to prepare specific concentrations.
The operation process comprises the following steps:
1. the desired reaction substrate was prepared using freshly prepared buffer.
2. The desired coenzyme factor is added to the above reaction system.
3. The kinase was added to the reaction and gently mixed.
4. The compounds dissolved in DMSO were added to the kinase-containing reaction system using an autosampler (Echo 550) and incubated at room temperature for 20min.
5. 33P-ATP (final specific activity concentration of 0.01. Mu. Ci/. Mu.l) was added to the kinase reaction system to initiate the reaction.
6. The reaction was incubated at room temperature for 2 hours.
7. Radioactivity was detected by the filter-binding method.
Data are expressed as the percentage of kinase in the test group relative to the DMSO solvent control group, i.e., the percentage of kinase activity remaining in the sample, and the results are as follows.
Figure BDA0003162716170000051
The data show that 0.1. Mu.M of the compounds of the invention have inhibitory activity against a variety of mutant kinases.
Example 2
Enzyme inhibitory activity reactants: basic buffer solution: 20mM Hepes (pH 7.5), 10mM MgCl 2 ,1mM EGTA,0.02％Brij35,0.02mg/ml BSA,0.1mM Na 3 VO 4 2mM DTT,1% DMSO. The required cofactors are added separately to each kinase reaction. Compound treatment: the compounds of the invention were dissolved in 100% DMSO to specific concentrations and diluted using an Integra Viaflo.
The operation process comprises the following steps:
1. the desired reaction substrate was prepared using freshly prepared buffer.
2. The desired coenzyme factor is added to the above reaction system.
3. The kinase was added to the reaction and gently mixed.
4. The compounds dissolved in DMSO were added to the kinase-containing reaction system using an autosampler (Echo 550) and incubated at room temperature for 20min.
5. 33P-ATP (final specific activity concentration of 0.01. Mu. Ci/. Mu.l) was added to the kinase reaction system to initiate the reaction.
6. The reaction was incubated at room temperature for 2 hours.
7. Radioactivity was detected by the filter-binding method.
Data are expressed as the percentage of kinase in the test group relative to the DMSO solvent control group, i.e., the percentage of kinase activity remaining in the sample. Curve fits and IC50 values were obtained using Prism (GraphPad software) and the results are given in the table below.
Figure BDA0003162716170000061
The compound has obvious inhibition effect on rare mutant G719X series kinase; the compound has obvious inhibition effect on kinase of refractory mutation (20 insX); the compound has obvious inhibition effect on ERBB2 mutant kinase.
Example 3
Proliferation inhibitory Activity of different EGFR and HER2 mutant type Ba/F3 cell lines
Test procedure
1) Taking logarithmically grown cells, centrifuging, discarding culture supernatant, and re-suspending the centrifuged cells in a fresh RPMI1640 culture medium at a cell density of 2 × 10e4/ml;
2) Inoculating the resuspended cells into a 96-well cell culture plate with a white wall transparent bottom, inoculating two culture plates with 100 ul/well cell suspension, and placing the culture plates in a 37-degree cell culture box for overnight culture;
3) Taking one 96-well plate inoculated with the cells on the next day, adding 100 ul/well cell titer glo detection reagent, standing for 60 minutes, reading a numerical value, and defining the numerical value as G0 data;
4) Another plate was taken and added with 10ul concentration of compounds diluted in a gradient starting at 1uM or 0.5uM (1 x final concentration in 96 well plates) and 9 concentration gradients diluted 3-fold and additional DMSO control wells set and incubated for a further 72 hours at 37 ℃ cell culture incubator;
5) Taking the 96-well plate treated by the compound for 72 hours out of the incubator, adding 100 ul/well cell titer glo detection reagent, standing for 60 minutes, reading the value, and defining as G3 data;
6) The% Proliferation = (average G3-G0 of test compound wells)/(average G3-average G0 of DMSO control wells) per well was calculated as follows for each well as 100;
7) Gradient curves of cell proliferation were fitted using Prism Graphpad software according to the proliferation rate and concentration corresponding to each gradient concentration well, and GI50 of the compound (GI 50 is defined as the concentration of the compound corresponding to the cell proliferation rate of 50%) was calculated, and the results are shown in the following table.
Figure BDA0003162716170000071
Figure BDA0003162716170000081
The compound has obvious inhibition effect on cell proliferation of G719X mutation, 20insX mutation and ERBB2 mutation; the compound of the invention has weak inhibitory effect on EGFR WT and has stronger selectivity.
Comparative example 1
With reference to the activity test assay method of example 3, the present invention further determined the cell proliferation inhibitory activity of compound N- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-8 (7H) -pteridinyl) phenyl) acrylamide (compound B), and compound N- (3- (2- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide (compound C) on partial mutation kinases.
Figure BDA0003162716170000082

Claims (10)

  1. Use of n- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease containing at least one of an EGFR 20insX mutation, an EGFR G719X mutation, and an ERBB2 mutation.
  2. 2. The use of claim 1, wherein the EGFR 20insX mutation is at least one mutation selected from the group consisting of EGFR V774-C775insX mutation, EGFR H773-V774insX mutation, EGFR P772-H773insX mutation, EGFR N771-P772insX mutation, EGFR D770-N771insX mutation, and EGFR V769-D770insX mutation.
  3. 3. The use of claim 2, wherein the EGFR 20insX mutation is at least one mutation selected from the group consisting of EGFR H773-V774insX mutation, EGFR P772-H773insX mutation, EGFR D770-N771insX mutation, and EGFR V769-D770insX mutation.
  4. 4. Use according to any one of claims 1 to 3, wherein X represents an amino acid or a combination of two or more amino acids.
  5. 5. The use of claim 2, the EGFR 20insX mutation comprising: at least one of EGFR V769_ D770insASV mutation, EGFR V769_ D770insDNP mutation, EGFR D770_ N771insNPG mutation, EGFR D770_ N771insG mutation, EGFR D770_ N771insNPH mutation, EGFR D770_ N771insSVD mutation, EGFR H773_ V774insPH mutation and EGFR H773_ V774insH mutation.
  6. 6. The use of claim 1, wherein the EGFR G719X mutation comprises: EGFR G719A mutation, EGFR G719S mutation, EGFR G719D mutation, EGFR G719C mutation.
  7. 7. The use of claim 1, wherein the ERBB2 mutation comprises: ERBB 2D 769Y mutation, ERBB 2V 777_ G778insCG mutation and ERBB 2V 777L mutation.
  8. Use of n- (3- (2- ((2-methoxy-4- (4-methyl-1-piperazinyl) phenyl) amino) -7-oxo-6-phenyl-8 (7H) -pteridinyl) phenyl) acrylamide, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease, optionally containing an EGFR L861Q mutation, an EGFR S768I mutation.
  9. 9. The use according to claim 1 or 8, wherein the disease is cancer.
  10. 10. The use according to claim 9, wherein the cancer is non-small cell lung cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer.
CN202110803492.8A 2021-07-14 2021-07-14 Novel use of EGFR inhibitor Pending CN115607551A (en)

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PCT/CN2022/105243 WO2023284747A1 (en) 2021-07-14 2022-07-12 Novel use of egfr inhibitor

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279173A (en) * 2015-05-29 2017-01-04 华东理工大学 Pteridinone derivant is as the application of EGFR inhibitor
CN108721298A (en) * 2017-04-19 2018-11-02 华东理工大学 As the pyrimido heterocyclic compound of bruton's tyrosine kinase inhibitor and its application

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