Discovery of YK-029A, a novel mutant EGFR inhibitor targeting both T790 M and exon 20 insertion mutations, as a treatment for NSCLC

Although traditional EGFR-TKIs have advanced the treatment landscape of NSCLC with sensitive driver mutations (del19 or L858R), some NSCLC patients with EGFR exon 20 insertion mutations have been left with few effective therapies. The development of novel TKIs is still in progress. Herein, we describe the structure-guided design of a novel selective and orally bioavailable inhibitor, YK-029A, which could overcome both the T790 M mutations and exon 20 insertion of EGFR. YK-029A inhibited EGFR signaling, suppressed sensitive mutations and ex20ins of EGFR-driven cell proliferation, and was largely effective with oral administration in vivo. Furthermore, YK-029A exhibited significant antitumor activity in EGFRex20ins-driven patients-derived xenograft (PDX) models, preventing tumor progression or causing tumor regression at well-tolerated dosages. Based on the outcomes of preclinical efficacy and safety studies, YK-029A will enter phase Ⅲ clinical trials for the treatment of EGFRex20ins NSCLC. [Display omitted] •Computer-aided drug design of a novel selective and orally bioavailable EGFR mutant TKI.•YK-029A could inhibit both T790 M and ex20ins of EGFR mutants.•YK-029A exhibited significant antitumor efficacy in EGFRLR/TM CDX and EGFRex20ins-driven PDX models.•In pre-clinical GLP toxicity studies in rats, high oral exposures of YK-029A achieved suitable safety margins.