CO-1686 is a novel, irreversible and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR including T790M(IC50=21 nM).

CO-1686 is a potent inhibitor of EGFR L858R/T790M kinase (kinact/Ki = (2.41 ± 0.30) x 105 M-1s-1) and is approximately 22-fold selective over WT EGFR (kinactt/Ki = (1.12 ± 0.14) x 104 M-1s-1). CO-1686 potently inhibited proliferation in the mutant-EGFR NSCLC cellswith GI50 values ranging from 7 - 32 nM. In comparison, the GI50 value for A431 cells, an epidermoid cell line that is driven by amplified WT EGFR(19), was 547 nM. Two cell lines

expressing WT EGFR in the presence of an N- or KRAS mutation (NCI-H1299 and NCI-H358,

respectively) were inhibited by CO-1686 at a concentration of 4275 and 1806 nM, respectively.