Capmatinib

INCB28060 / capmatinib is a potent c-MET inhibitor, which shows excellent selectivity in a broad panel of 442 kinases.  Sub nM-activity is observed at wt and mutant (M1250T, Y1235D) c-Met, with most-active off targets being IRAK1 (500nM) and AXL (1100nM). Capmatibib resistance is observed in clinically-relevant mutants D1228 and Y1230, observed in lung cancer.  The molecule has physchem properties supporting good cell permeability, and shows potent inhibition of c-MET signalling in a range of cell lines. Capmatinib was tested against >600 cancer cell lines, (only) 13 cell lines were sensitive, these all showed MET gene amplification or high expression of HGF (Met ligand). In Vivo, a concentration-dependent effect on phospho c-Met is observed, although detailed pharmacokinetic data is not provided, and anti-tumour effects are observed in several MET amplified, overexpressed or mutated models.

Capmatinib (INC280) is an exceptionally potent and kinome-selective inhibitor of c-Met. The on-target potency is sub-nM. Using both a limited panel of 57 kinases and the larger 442 kinases KINOMEscan panels, no off-target kinases within >1000-fold potency (Kd or IC50) were identified. The kinome selectivity is consistent with its narrow spectrum of anti-proliferative activities in a large cell line panel screen (>600 cell lines), where the sensitive cell lines are characterized by MET amplification, MET overexpression, MET exon 14 skipping mutations, or MET activation via expression of the ligand HGF. The compound has acceptable PK and has demonstrated dose- and time-dependent inhibition of phospho-c-MET in vivo. Tumour growth inhibition and even regression has been achieved when dosed orally at 1 mg/kg up to 30 mg/kg BID. When using this compound in vitro, please note that c-MET signalling is potently inhibited in the nM range, however, very few cell lines (e.g., EBC-1, MKN45, SNU-5) critically depend on c-MET for proliferation. For others, growth inhibition curves are often shallow and do not reach 100%.