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%.
14 Dec 2020 )