Discovery of a Novel, Selective and Irreversible Inhibitor (Abivertinib) of Mutated EGFR and T790M-induced Resistance for the Treatment of NSCLC

Three chemical series of heterocyclic small molecules were designed and synthesized as the 3rd generation EGFR inhibitors. Detailed structure-activity relationship (SAR) studies and lead optimization (from 1a to 4d) were descripted. With the support of molecular modeling and evaluation through biochemical and cellular assays, liver microsomal/ plasma/ blood stability studies, preliminary rat PK screening and in vivo animal models, pyrrolopyrimidine-based compound 4d (abivertinib, AC0010), a novel potent and highly selective irreversible EGFR inhibitor, was discovered.Unlabelled Image