CN117919235A - Application of naphthalamide compound in treating KRAS mutation related diseases - Google Patents

Application of naphthalamide compound in treating KRAS mutation related diseases Download PDF

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CN117919235A
CN117919235A CN202311381221.3A CN202311381221A CN117919235A CN 117919235 A CN117919235 A CN 117919235A CN 202311381221 A CN202311381221 A CN 202311381221A CN 117919235 A CN117919235 A CN 117919235A
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cancer
kras
compound
tumor
kras mutation
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丁健
段文虎
谢华
詹正生
耿美玉
杨汉煜
吕永聪
童林江
赵璐
吴彦波
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Shanghai Runshi Pharmaceutical Technology Co ltd
Shanghai Institute of Materia Medica of CAS
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Shanghai Runshi Pharmaceutical Technology Co ltd
Shanghai Institute of Materia Medica of CAS
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Organic Chemistry (AREA)
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Abstract

The invention relates to application of a naphthalamide compound in treating KRAS mutation related diseases. In particular, the invention discloses the use of a compound (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for treating KRAS mutation related diseases, especially KRAS mutant tumors, wherein the compound can effectively inhibit the growth of KRAS mutant tumors, especially KRAS G12C mutant tumors and KRAS G12D mutant tumors.

Description

Application of naphthalamide compound in treating KRAS mutation related diseases
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a naphthalamide compound in preparation of a medicine for treating KRAS mutation related diseases, in particular KRAS mutation tumors.
Background
KRAS is one of the most frequent genes in human tumors, involved in driving the development and progression of nearly one third of human malignancies, and is closely related to tumor prognosis. KRAS mutations account for about 90% of pancreatic cancers, 30% -40% of colon cancers, 15% -20% of lung cancers, and KRAS mutations can also occur in other tumors such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer and breast cancer. KRAS mutations can produce six different mutant forms, with KRAS G12D, G V and G12C mutations being the most common and G12A, G12R and G12S mutations being less common. Research on small molecule inhibitors of KRAS mutations has been slow for many years, with KRAS becoming a "non-patentable" target.
Currently, small molecule inhibitors targeting KRAS G12C mutations are making breakthroughs. AMG 510 is a small molecule inhibitor developed by Amgen and marketed by FDA in month 2021, and is currently the only one available small molecule inhibitor for KRAS, and its mechanism of action is to lock KRAS in an inactive GDP-binding state by binding to G12C cysteine, specifically and irreversibly inhibiting KRAS G12C. MRTX849 is an oral small molecule inhibitor developed by Mirati Therapeutics against KRAS G12C mutation, having a similar structural backbone to AMG 510, currently in the pre-registered (pre-registered) stage. In addition, a number of KRAS G12C inhibitors are in clinical stages, including JDQ-443 (Novartis, inc., clinical I/II), GFH-925 (China's medical & Xindada, clinical I/II), D-1553 (China's beneficial organisms, clinical I/II), JAB-21822 (China's additional department, clinical I/II), ARS-3248 (China's additional department, clinical I), BI-1823911 (Boehringer Ingelheim, clinical I), GDC-6036 (Roche, clinical I) and LY-3537982 (Eli Lilly, clinical I). However, inhibitors targeting KRAS G12D mutation have had very limited studies, no compound has entered clinical studies, MRTX1133 developed by Mirati Therapeutics is a currently reported small molecule inhibitor against KRAS G12D, now in preclinical research stages.
Currently, the type of KRAS mutation in patients is determined clinically by means of gene detection and then drug targeting therapy is performed, but the patients with KRAS G12D mutation are currently in a drug-free treatable stage, so that safe and effective drug treatment schemes are urgently needed for such patients, even for patients with other KRAS mutations, such as G12V, G12A, G R or G12S mutation.
The compound (I) is disclosed in CN104860885A for the first time, the structural formula is shown as the following formula (I),
The compound (I) is a VEGFR inhibitor with excellent activity and can inhibit the proliferation of tumor cells. The prior art does not report its effect on KRAS mutation related diseases, in particular KRAS mutant tumours.
Disclosure of Invention
The invention aims to provide the application of a naphthalene amide compound in treating KRAS mutation related diseases, especially KRAS mutation tumors.
In a first aspect of the invention there is provided the use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of KRAS mutation related diseases;
the compound (I) has the following structure:
In another preferred embodiment, the KRAS mutation related disease is a KRAS mutant tumour.
In another preferred embodiment, the KRAS mutant tumour is selected from the group consisting of: KRAS G12D mutant tumor, KRAS G12V mutant tumor, KRAS G12C mutant tumor, KRAS G12A mutant tumor, KRAS G12R mutant tumor, KRAS G12S mutant tumor.
In another preferred embodiment, the KRAS mutation related disease is selected from the group consisting of: KRAS G12C mutant tumor, KRAS G12D mutant tumor.
In another preferred embodiment, the KRAS mutation related disease is selected from the group consisting of: pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, breast cancer, endometrial cancer, skin cancer, ovarian cancer, gastric cancer, urinary tract cancer, soft tissue sarcoma, esophageal cancer, multiple myeloma, prostate cancer, renal cancer, neuroendocrine tumor of the gastrointestinal tract, gastrointestinal stromal tumor, head and neck cancer, glioma, salivary gland cancer, bone cancer, anal cancer, thyroid cancer, melanoma, mature B-cell tumor, small intestine cancer, ampulla cancer.
In another preferred embodiment, the lung cancer is selected from the group consisting of: small cell lung cancer, non-small cell lung cancer, and lung adenocarcinoma.
In another preferred embodiment, the KRAS mutation related disease is selected from the group consisting of: pancreatic cancer, lung cancer.
In another preferred embodiment, the KRAS mutation related disease is KRAS G12D mutated pancreatic cancer.
In another preferred embodiment, the KRAS mutation related disease is KRAS G12C mutated lung cancer.
In another preferred embodiment, the KRAS mutation related disease is KRAS G12C mutated non-small cell lung cancer.
In another preferred embodiment, the patient suffering from a KRAS mutation related disease is a human.
In a second aspect of the present invention, there is provided a pharmaceutical composition for the treatment of a KRAS mutation-related disease comprising a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
the compound (I) has the following structure:
In another preferred embodiment, the pharmaceutical composition is an oral formulation.
In another preferred embodiment, the KRAS mutation related disease is as described above.
In a third aspect of the invention, there is provided a method of treating a KRAS mutation related disease comprising the steps of:
1) Administering a therapeutically effective amount of compound (I) or a pharmaceutically acceptable salt thereof to a patient in need of treatment for KRAS mutation related diseases;
the compound (I) has the following structure:
in another preferred embodiment, the step 1) further comprises the following steps:
The KRAS mutation type of the patient is determined by adopting a gene detection mode.
In another preferred embodiment, the KRAS mutation related disease is as described above.
In a fourth aspect of the invention, there is provided a method of treating a KRAS mutation related disease comprising the steps of:
1) The pharmaceutical composition according to the second aspect of the invention is administered to a patient in need of treatment for a KRAS mutation related disease.
In another preferred embodiment, the step 1) further comprises the following steps:
The KRAS mutation type of the patient is determined by adopting a gene detection mode.
In another preferred embodiment, the KRAS mutation related disease is as described above.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Through long-term and intensive researches, the inventor surprisingly discovers that the compound (I) has remarkable inhibitory activity on KRAS mutation related diseases, especially KRAS mutation tumors, can remarkably inhibit the growth of the KRAS mutation tumors, and is hopeful to develop effective antitumor drugs. On this basis, the inventors completed the present invention.
"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds.
The mode of administration of the pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
Correspondingly, the medicine of the invention can be prepared into various clinically acceptable dosage forms, including oral dosage forms, injection dosage forms, local administration dosage forms or external dosage forms, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., antineoplastic agents).
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
The compound of the invention can be singly prepared into medicines or can be combined with other pharmaceutically acceptable compounds (such as antitumor medicines) to prepare medicines. When the compound of the invention is combined with other pharmaceutically acceptable compounds (such as antitumor drugs) to prepare drugs, different active ingredients can be respectively prepared into pharmaceutically acceptable preparations, and the preparations are further combined and packaged to obtain the final product; or in the case of pharmaceutically acceptable salts, the different active ingredients are contained in the same formulation product.
In the present invention, the therapeutically effective amount refers to a pharmaceutically effective dosage, i.e., an amount of the active compound sufficient to significantly improve the condition without causing serious side effects. For a person weighing 60kg, the daily dosage is usually 0.01 to 2000mg, preferably 1 to 500mg. The preparation can be administered once a day in a single dose, can be administered in multiple times per day, or can be used at intervals. The particular dosage and frequency of administration should take into account factors such as the route of administration, the health of the patient, etc., which can be determined by a skilled practitioner according to routine skill.
In some embodiments, a mammal (e.g., a human) in need of treatment is subjected to gene testing for KRAS mutations to determine the patient's KRAS mutation type prior to administration of compound (I) of the present invention or a pharmaceutically acceptable salt thereof or a medicament containing compound (I) or a pharmaceutically acceptable salt thereof to the mammal (e.g., human) in need of treatment. The prior art has many methods for detecting KRAS mutation gene, including direct sequencing, pyrosequencing, high resolution melting curve analysis (high-resolution melting, HRM), amplification block mutation system (amplification refractory mutation system, ARMS), fluorescent quantitative PCR (real-time PCR), polymerase chain reaction-single strand conformational polymorphism analysis (PCR-SINGLE STRAND conformation polymorphism, PCR-SSCP), complex amplification polymerase chain reaction at low denaturation temperature (co-amplification at lower denaturation temperature PCR, COLD-PCR), and high performance liquid chromatography. Those skilled in the art can choose the one according to the need.
Compared with the prior art, the invention has the following main advantages:
(1) Compared with the AMG510 of the marketed KRAS G12C targeting drug, MRTX1133 of the KRAS G12D targeting drug in the preclinical research stage is simpler to synthesize;
(2) AMG510 can only treat KRAS G12C-related tumors, MRTX1133 is effective only on KRAS G12D-related tumors, and the compound (I) disclosed by the invention is effective on KRAS G12C and KRAS G12D-related tumors;
(3) In vivo studies showed that:
1) The compound (I) has remarkable inhibitory activity on the growth of KRAS G12D mutant human pancreatic cancer PANC-1 cell nude mice transplanted tumor, and no effective therapeutic drug exists in the field at present. The compound (I) is orally taken twice a day in the groups of 10mg/kg and 5mg/kg, so that the growth of subcutaneous transplantation tumor of the human pancreatic cancer PANC-1 nude mice is obviously inhibited, and the percentage of T/C obtained on the 30 th day is 18.2% and 27.3% respectively; in the experiment, each group of mice was in good condition.
2) The compound (I) has obvious tumor inhibiting activity on KRAS G12C mutant human non-small cell lung cancer NCI-H358 cell nude mice transplantation tumor. The compound (I) is orally taken for 2 times per day at a dose of 10mg/kg, so that the growth of subcutaneous transplantation tumor of non-small cell lung cancer NCI-H358 nude mice is obviously inhibited, and the percentage of T/C obtained on the 21 st day is 17.6%; the oral administration was 2 times per day at a dose of 10mg/kg, with a percentage of T/C obtained at day 54 of 9.2%. In the experiment, each group of mice was in good condition.
The experiment shows that the compound (I) or the pharmaceutically acceptable salt thereof can obviously inhibit the tumor growth of KRAS mutation (especially KRAS G12C mutation and/or KRAS G12D mutation), and is expected to develop effective antitumor drugs.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Experimental material sources or formulations:
compound (I): prepared as described in example 21 with reference to CN 104860885A.
The reagents and raw materials used in the experiments are all purchased commercially or prepared by themselves.
The preparation method of the in vivo test object is shown in table a:
Table A
Raw and auxiliary materials Dosage of
Compound (I) 60mg
Medium chain triglycerides 1ml
Polyoxyethylene 40 hydrogenated castor oil 1.5ml
Diethylene glycol monoethyl ether 2.5ml
Oleic acid 1ml
Ethanol: ethyl acetate (1:1) as a latent solvent 15～20ml
Blank formulation: the formulation is as in Table A, except that compound (I) is absent.
The latent solvent is removed by evaporation in the preparation process, and the obtained test object and blank preparation do not contain the latent solvent.
The preparation or blank preparation containing compound (I) is diluted with water to a desired concentration or desired volume immediately before use.
Cell strain source and obtaining: human pancreatic cancer PANC-1 and human non-small cell lung carcinoma NCI-H358 were purchased from ATCC (American type culture Collection).
Example 1: compound (I) has effect of inhibiting growth of KRAS G12D mutant human pancreatic cancer PANC-1 cell nude mice transplantation tumor
1. Experimental method
Experimental animals: BALB/c nude mice, females, age: 3-4 weeks of age. The KRAS G12D mutant human pancreatic cancer PANC-1 cells are inoculated under the right armpit skin of a nude mouse, the cell inoculation amount is 5 multiplied by 10 6/mouse, and the mice are randomly grouped when the average tumor volume reaches about 100mm 3: (1) group of compounds (I): compound (I) was orally administered twice daily for 30 consecutive days at doses of 5mg/kg and 10mg/kg, respectively; (2) The solvent control group was given a blank preparation of the same volume as that of the 10mg/kg compound (I) administration group, orally administered twice daily for 30 consecutive days.
During the experiment, the diameter of the transplanted tumor was measured 2 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=0.5×a×b 2, where a, b represent length, width, respectively; relative tumor volume (relative tumor volume, RTV), the calculation formula is: rtv=v t/V0; wherein V 0 is the tumor volume measured at the time of divided administration (i.e., d 0), and V t is the tumor volume at each measurement; the evaluation indexes of the antitumor activity are as follows: relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (T RTV/CRTV)×100％,TRTV: treatment group RTV; C RTV: solvent control group RTV.
2. Experimental results
The results are shown in Table 1, and the compound (I) 10mg/kg and 5mg/kg groups, orally administered twice daily, significantly inhibited the growth of human pancreatic cancer PANC-1 nude mice subcutaneous transplants, with the T/C percentages obtained on day 30 being 18.2% and 27.3%, respectively. In the experiment, each group of mice was in good condition. In view of the fact that no effective therapeutic drug for KRAS G12D mutant human pancreatic cancer exists in the prior art, the compound (I) provided by the invention shows outstanding therapeutic activity on human pancreatic cancer PANC-1 nude mice transplantation tumor, so that the compound (I) is expected to develop an effective therapeutic drug for KRAS G12D mutant human pancreatic cancer.
Treatment of human pancreatic cancer PANC-1 nude mice transplantation tumor with Compound (I) of Table 1
Experimental data were counted using a t-test analysis and compared to the solvent control group, p <0.05, p <0.01, p <0.001.
Example 2: compound (I) has inhibitory effect on KRAS G12C mutant human non-small cell lung cancer NCI-H358 cell nude mice transplantation tumor growth (21 days of administration)
1. Experimental method
Experimental animals: BALB/c nude mice, females, age: 3-4 weeks of age. Human non-small cell lung cancer NCI-H358 cells mutated by KRAS G12C are inoculated under the armpit skin on the right side of a nude mouse, the cell inoculation amount is 5 multiplied by 10 6/mouse, and after the average tumor volume reaches about 100mm 3, the mice are randomly grouped: (1) group of compounds (I): compound (i) was orally administered twice daily for 21 days at doses of 10mg/kg and 5mg/kg, respectively; (2) The solvent control group was given a blank preparation of the same volume as that of the 10mg/kg compound (I) administration group, orally administered twice daily for 21 days.
During the experiment, the diameter of the transplanted tumor was measured 2 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=0.5×a×b 2, where a, b represent length, width, respectively; relative tumor volume (relative tumor volume, RTV), the calculation formula is: rtv=v t/V0; wherein V 0 is the tumor volume measured at the time of divided administration (i.e., d 0), and V t is the tumor volume at each measurement; the evaluation indexes of the antitumor activity are as follows: relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (T RTV/CRTV)×100％,TRTV: treatment group RTV; C RTV: solvent control group RTV.
2. Experimental results
The results are shown in Table 2, and the compound (I) 10mg/kg and 5mg/kg groups, orally administered twice daily, significantly inhibited the growth of non-small cell lung cancer NCI-H358 nude mice subcutaneous transplants, with the T/C percentages obtained on day 21 being 17.6% and 29.4%, respectively. In the experiment, all groups of mice are good in state and do not show obvious toxic reaction. The compound (I) has outstanding tumor inhibiting activity on KRAS G12C mutant tumor.
Table 2 therapeutic Effect of Compound (I) on human non-Small cell lung cancer NCI-H358 nude mice transplantation tumor
Experimental data were counted using a t-test analysis, with p <0.05, < p <0.01, < p <0.001, compared to the solvent control group.
Example 3: compound (I) has inhibiting effect on KRAS G12C mutant human non-small cell lung cancer NCI-H358 cell nude mice transplantation tumor growth (54 days of administration)
1. Experimental method
Experimental animals: BALB/c nude mice, females, age: 3-4 weeks of age. Human non-small cell lung cancer NCI-H358 cells mutated by KRAS G12C are inoculated under the armpit skin on the right side of a nude mouse, the cell inoculation amount is 5 multiplied by 10 6/mouse, and after the average tumor volume reaches about 100mm 3, the mice are randomly grouped: (1) group of compounds (I): compound (i) was orally administered twice daily for 54 days at doses of 10mg/kg and 5mg/kg, respectively; (2) The solvent control group was given a blank formulation of the same volume as that of the 10mg/kg compound (I) administration group, orally administered twice daily for 54 days.
During the experiment, the diameter of the transplanted tumor was measured 2 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=0.5×a×b 2, where a, b represent length, width, respectively; relative tumor volume (relative tumor volume, RTV), the calculation formula is: rtv=v t/V0; wherein V 0 is the tumor volume measured at the time of divided administration (i.e., d 0), and V t is the tumor volume at each measurement; the evaluation indexes of the antitumor activity are as follows: relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (T RTV/CRTV)×100％,TRTV: treatment group RTV; C RTV: solvent control group RTV.
2. Experimental results
The results are shown in Table 3, and the compound (I) 10mg/kg and 5mg/kg groups, orally administered twice daily, significantly inhibited the growth of non-small cell lung cancer NCI-H358 nude mice subcutaneous transplants, with the T/C percentages obtained on day 54 being 9.2% and 10.5%, respectively. In the experiment, all groups of mice are good in state and do not show obvious toxic reaction. The compound (I) has outstanding tumor inhibiting activity on KRAS G12C mutant tumor.
TABLE 3 therapeutic Effect of Compound (I) on human non-Small cell lung cancer NCI-H358 nude mice transplantation tumor
Experimental data were counted using a t-test analysis, with p <0.05, < p <0.01, < p <0.001, compared to the solvent control group.
The experiment shows that the compound (I) or the pharmaceutically acceptable salt thereof can obviously inhibit the tumor growth of KRAS mutation (especially KRAS G12C mutation and/or KRAS G12D mutation), and is expected to develop effective antitumor drugs.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (8)

1. The use of compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of KRAS mutation-related diseases;
the compound (I) has the following structure:
2. The use of claim 1, wherein the KRAS mutation related disease is a KRAS mutant tumour.
3. The use of claim 2, wherein the KRAS mutation related disease is selected from the group consisting of: KRAS G12C mutant tumor, KRAS G12D mutant tumor.
4. The use according to any one of claims 1 to 3, wherein the KRAS mutation related disease is selected from the group consisting of: pancreatic cancer, colorectal cancer, lung cancer, cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, breast cancer, endometrial cancer, skin cancer, ovarian cancer, gastric cancer, urinary tract cancer, soft tissue sarcoma, esophageal cancer, multiple myeloma, prostate cancer, renal cancer, neuroendocrine tumor of the gastrointestinal tract, gastrointestinal stromal tumor, head and neck cancer, glioma, salivary gland cancer, bone cancer, anal cancer, thyroid cancer, melanoma, mature B-cell tumor, small intestine cancer, ampulla cancer.
5. The use of claim 4, wherein the KRAS mutation related disease is selected from the group consisting of: pancreatic cancer, lung cancer.
6. The use of claim 1, wherein the KRAS mutation related disease is KRAS G12D mutated pancreatic cancer.
7. The use of claim 1, wherein the KRAS mutation-related disease is KRAS G12C mutated lung cancer.
8. The use of claim 1, wherein the KRAS mutation-related disease is KRAS G12C mutated non-small cell lung cancer.
CN202311381221.3A 2022-10-25 2023-10-24 Application of naphthalamide compound in treating KRAS mutation related diseases Pending CN117919235A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104860885B (en) * 2014-02-24 2017-11-17 中国科学院上海药物研究所 Naphthoyl aminated compounds, preparation method and use
US10238650B2 (en) * 2015-03-06 2019-03-26 Beyondspring Pharmaceuticals, Inc. Method of treating cancer associated with a RAS mutation
KR102641827B1 (en) * 2017-05-02 2024-03-04 노파르티스 아게 combination therapy
CN113827727A (en) * 2020-06-24 2021-12-24 上海交通大学医学院附属瑞金医院 Application of PTPN2 inhibitor in KRAS mutant tumor
CN115215847A (en) * 2021-04-16 2022-10-21 中国科学院上海药物研究所 KRAS-SOS1 inhibitor, preparation method and application thereof

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