CO-1686 is an irreversible and orally delivered inhibitor of mutant EGFR with IC50 value of < 0.51 nM for recombinant EGFR L858R/T790M [1].
CO-1686 covalently modified Cys797 in the ATP binding pocket of the EGFR kinase. It also modified this residue in the EGFR L858R/T790M kinase domain. In the in vitro assay, CO-1686 potently inhibited EGFR L858R/T790M kinase with about 22-fold selectivity over wild-type EGFR. Among the 23 targets treated with CO-1686, EGFR del19, T790M, L858R/T790M and L858R mutants demonstrated the highest inhibition degree. In 4 NSCLC cell lines expressing mutant EGFR (HCC827, PC9, HCC827-EPR and NCI-H1975), CO-1686 potently inhibited cell proliferation with GI50 values of 7-32 nM. CO-1686 also inhibited some minor EGFR mutants including G719S, the exon 19 insertion and L861Q. In mice with NCI-H1975 xenografts, 100 mg/kg/day administration of CO-1686 caused tumor regressions [2].
References:
[1] Walter A O, Tjin R, Haringsma H, et al. CO-1686, an orally available, mutant-selective inhibitor of the epidermal growth factor receptor (EGFR), causes tumor shrinkage in Non-Small Cell Lung Cancer (NSCLC) with T790M resistance mutations. Mol Cancer Ther, 2011, 10(11 Suppl).
[2] Walter A O, Sjin R T T, Haringsma H J. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC.