卡马替尼

MET small molecule inhibitor

Capmatinib(Synonyms: INC280; INCB28060) is a competitive inhibitor with very potent and selective activity against MET compared to other kinases. It has been shown in vitro that cell lines made resistant to erlotinib, an EGFR inhibitor, could be resensitized after capmatinib treatment. Results from a phase Ib/II study of patients with EGFR-mutated, MET-dysregulated NSCLC have shown promising responses to a combination of capmatinib and gefitinib (EGFR TKI) following disease progression from an only EGFR TKI treatment regimen. Recommended phase II dose was determined to be capmatinib 400 mg twice/day and gefitinib 250 mg once/day. Most common adverse events were nausea, peripheral edema, decreased appetite, rash, and increased amylase and lipase levels.

Description

INCB 28060 is an inhibitor of heptatocyte growth factor receptor (HGFR, also known as c-Met), potently blocking in vitro kinase activity (IC₅₀ = 0.13 nM) as well as constitutive or HGF-stimulated activity in cells (IC₅₀ values range from 0.3 to 1.1 nM). It blocks cell proliferation and migration or induces apoptosis in different types of cancer cells. INCB 28060 is orally bioavailable and inhibits the growth of HGFR-dependent tumors in mice. It also improves efficacy of gemcitabine (Item No. 11690) in a mouse pancreatic cancer model and reduces migration and adhesion in ovarian cancer cell models.

Capmatinib is a competitive inhibitor with very potent and selective activity against MET compared to other kinases.

Uses

2-Fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide is used in the preparation of a combination formulation with allosteric SHP2 inhibitor TNO155. Used in treatment of non-small cell lung cancer with specific mutations (those that lead to mesenchymal-epithelial transition or MET exon 14 skipping).

Side effects

Most common adverse events were nausea, peripheral edema, decreased appetite, rash, and increased amylase and lipase levels.

in vitro

It has been shown in vitro that cell lines made resistant to erlotinib, an EGFR inhibitor, could be resensitized after capmatinib treatment. Results from a phase Ib/II study of patients with EGFR-mutated, MET-dysregulated NSCLC have shown promising responses to a combination of capmatinib and gefitinib (EGFR TKI) following disease progression from an only EGFR TKI treatment regimen. Recommended phase II dose was determined to be capmatinib 400 mg twice/day and gefitinib 250 mg once/day.