Macrocyclic compounds and uses thereof
Inventors
Cui, Jingrong Jean • ROGERS, Evan W. • Ung, Jane • WHITTEN, JEFFREY • Zhai, Dayong • Deng, Wei • Zhang, Xin • HUANG, Zhongdong • Liu, Jing • Zhang, Han
Assignees
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Publication Number
US-11981684-B2
Publication Date
2024-05-14
Expiration Date
Abstract
The present disclosure relates to certain macrocyclic compounds that inhibit SRC and MET, and/or CSF1R, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat cancer.
Core Innovation
The invention relates to macrocyclic Formula I compounds and defined compound classes that inhibit SRC and MET and/or CSF1R, and that are described in the context of inhibiting HGF/MET signaling and broader polypharmacology. The subject matter also includes pharmaceutically acceptable salts, stereoisomers, racemates, enantiomers, diastereomers, geometric isomers, isotopically labeled compounds, prodrugs, active metabolites, and isotopically labeled analogs for imaging and metabolic studies.
The problem addressed is the role of HGF/MET signaling in tumor growth, invasion, metastasis, and therapy resistance, together with regulation by CSF1 and tumor-associated macrophages, including M2 macrophages. The background links Src and MET to tumor progression and therapy resistance, and the document states an unmet need for polypharmacology that can address these pathways together.
The claimed treatment context focuses on administering a therapeutically effective amount of the defined compound or a pharmaceutically acceptable salt to treat solid cancer in a patient in need thereof. The disclosed scope includes metastatic cancer, lung cancer limited to non-small cell lung cancer, cancer having Met amplification, and cancer having a Met exon 14 mutation.
Claims Coverage
Independent claim coverage is directed to methods of treatment by administering a therapeutically effective amount of a compound defined by a chemical structure or Formula I, or a pharmaceutically acceptable salt, to specified cancer patient populations. Across the independent claims, the inventive features focus on treatment of solid cancer generally, cancer having Met amplification, and cancer having a Met exon 14 mutation, with dependent limitations to metastatic cancer and non-small cell lung cancer.
Treating a solid cancer by administering a defined compound
A method of treating a solid cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof.
Treating Met amplification cancers by administering a defined compound
A method of treating a cancer having Met amplification in a patient in need thereof, comprising administering a therapeutically effective amount of a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof.
Treating Met exon 14 mutation cancers by administering a defined compound
A method of treating a cancer having a Met exon 14 mutation in a patient in need thereof, comprising administering a therapeutically effective amount of a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof.
The claims collectively cover administering Formula I macrocyclic or defined-structure compounds, or pharmaceutically acceptable salts, to treat solid cancers generally and cancers specifically characterized by Met amplification or Met exon 14 mutation, with dependent narrowing to metastatic cancer and non-small cell lung cancer.
Stated Advantages
Inhibits SRC and MET and/or CSF1R.
Inhibits HGF/MET signaling.
Addresses an unmet need for polypharmacology in cancer treatment related to tumor growth, invasion, metastasis, and therapy resistance.
Provides synergistic anti-tumor activity in combination settings with EGFR-targeted antibodies, small-molecule EGFR inhibitors, and PD-1 approaches.
Documented Applications
Method of treating a solid cancer in a patient, including metastatic cancer, by administering a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt.
Method of treating cancer having Met amplification in a patient by administering a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt.
Method of treating cancer having a Met exon 14 mutation in a patient by administering a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt.
Cancer-treatment context with EGFR inhibitors, including EGFR-targeted antibodies and small-molecule EGFR inhibitors, and PD-1 approaches.
Enzymatic kinase assay profiling and cellular proliferation/viability, phosphorylation inhibition of MET and downstream signaling including STAT3, ERK, and AKT, cell migration inhibition, and in vivo antitumor efficacy for Compound 5, including xenograft models, PDX models, and a syngeneic model, with pharmacodynamic MET phosphorylation readouts and combination activity with a PD-1 antibody.
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