KIN-8741 is a potent, selective type IIb c-Met kinase inhibitor with IC50 of 11 nM for both WT and D1228 N c-Met in cell viability assays utilized engineered Ba/F3-TPR-c-Met-WT and Ba/F3-TPR-c-Met-D1228N.
KIN-8741 exhibits subnanomolar potency in c-Met kinase assays (0.2 to 0.3 nM), demonstrates excellent selectivity in a full kinase panel of >600 kinases at 100 nM.
KIN-8741 broadly and potently inhibits the proliferation of Ba/F3-TPR-c-Met mutant cells, the D1228X and Y1230X mutations are inhibited in the single digit nanomolar EC50 range (except Y1230C EC50 = 13 nM).
KIN-8741 is the most potent c-Met inhibitor against D1228X/Y1230X mutations, compared with type II inhibitors (cabozantinib, glesatinib and merestinib).
KIN-8741 also potently inhibits back pocket mutations L1195X and F1200X (0.7–51 nM), which show varying degrees of resistance to other type II agents.
KIN-8741 (20-60 mg/kg, BID) displays potent antitumor activity against MET D1228N mutant model, and in MET gene amplification and exon14 deletion NSCLC models.