INCB28060

INCB28060, also known as Capmatinib and INC280, is a novel and ATP-competitive inhibitor of c-Met with IC50 of 0.13 nM.

c-Met, also named as hepatocyte growth factor receptor (HGFR) is a receptor tyrosine kinase that is essential for embryonic development and would healing. In many tumor cells, this molecular is overexpressed or mutated and was found to play important roles in tumor cell proliferation, survival, invasion, metastasis and angiogenesis.

In vitro, INCB28060 treatment effectively inhibited activation of c-MET and signaling in cancer cells. As a result, INCB28060 blocked cell proliferation of varying cell lines such as SNU-5 and S114. The cell migration of U-87MG and H441 cells were also highly inhibited1.

The role of c-met was studied using this inhibitor in mouse model. Oral administration of INCB28060 leads to inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models. Therefore, INCB28060 has the therapeutic potential in cancer treatment 1.

Reference:
1.   Liu X, Wang Q, Yang G, et al. A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17(22):7127-7138.

A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3.[Pubmed:21918175]

Clin Cancer Res. 2011 Nov 15;17(22):7127-38.

PURPOSE: The c-MET receptor tyrosine kinase plays important roles in the formation, progression, and dissemination of human cancer and presents an attractive therapeutic target. This study describes the preclinical characterization of INCB28060, a novel inhibitor of c-MET kinase. EXPERIMENTAL DESIGN: Studies were conducted using a series of in vitro and in vivo biochemical and biological experiments. RESULTS: INCB28060 exhibits picomolar enzymatic potency and is highly specific for c-MET with more than 10,000-fold selectivity over a large panel of human kinases. This inhibitor potently blocks c-MET phosphorylation and activation of its key downstream effectors in c-MET-dependent tumor cell lines. As a result, INCB28060 potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis in vitro. Oral dosing of INCB28060 results in time- and dose-dependent inhibition of c-MET phosphorylation and tumor growth in c-MET-driven mouse tumor models, and the inhibitor is well tolerated at doses that achieve complete tumor inhibition. In a further exploration of potential interactions between c-MET and other signaling pathways, we found that activated c-MET positively regulates the activity of epidermal growth factor receptors (EGFR) and HER-3, as well as expression of their ligands. These effects are reversed with INCB28060 treatment. Finally, we confirmed that circulating hepatocyte growth factor levels are significantly elevated in patients with various cancers. CONCLUSIONS: Activated c-MET has pleiotropic effects on multiple cancer-promoting signaling pathways and may play a critical role in driving tumor cell growth and survival. INCB28060 is a potent and selective c-MET kinase inhibitor that may have therapeutic potential in cancer treatment.

Capmatinib (INC280; INCB28060) is a potent, orally active, selective, and ATP competitive c-Met kinase inhibitor (IC50=0.13 nM). Capmatinib (INC280; INCB28060) potently inhibits c-MET-dependent tumor cell proliferation and migration and effectively induces apoptosis. Antitumor activity.

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