Discovery Of Hm61713 As An Orally Available And Mutant Egfr Selective Inhibitor

Introduction: Activating mutations of EGFR are well known as oncogenic driver mutations in lung adenocarcinoma. Currently, EGFR TKIs including Gefitinib and Erlotinib are used as the first line therapy in NSCLC patients harboring EGFR activating mutations. However, drug resistance caused by T790M mutation limits the efficacy of these 1st generation EGFR TKIs. Currently, some of the next generation EGFR TKIs are under investigation for the treatment of lung cancer patients having T790M mutation. In our current presentation, to obtain HM61713, an EGFR mutant selective inhibitor, as a clinical candidate and the evaluation of HM61713 for mutant EGFR cancer model will be introduced. Method: Novel analogues were designed and synthesized to find active compounds for the T790M mutation as well as EGFR activating mutations with good selectivity over wild- type EGFR. Finally, HM61713 was selected as a clinical candidate through multi-optimization processes including both in vitro and in vivo pharmacologcal studies. Results: HM61713 was designed as an irreversible kinase inhibitor having a Michael acceptor, which covalently binds to a cysteine residue near the kinase domain of mutant the EGFR. In a cell wash out test, HM61713 inhibited phospho-EGFR for a long duration with a half-life of over 24 hours. From in vitro study, HM61713 showed potent activities for H1975 (L858-T790M) and HCC827 (exon 19 del.) with GI50 values of 9.2 nM and 10 nM, respectively. Instead, it showed low potency for H358 (wild type EGFR NSCLC) with GI50 of 2,225 nM. In xenograft studies using H1975 and HCC827, HM61713 resulted in good efficacy without showing any side effects. Conclusion: HM61713 showed excellent in vitro and in vivo activities for H1975 harboring L858R-T790M mutation as well as HCC827 having exon 19 deletion mutation with selectivity over wild-type EGFR. Currently, HM61713 is undergoing phase I study (NCT01588145) for NSCLC patients after the failure of 1st generation EGFR TKIs in Korea. Citation Format: Kwang-Ok Lee, Mi Young Cha, Mira Kim, Ji Yeon Song, Jae-Ho Lee, Young Hoon Kim, Young-Mi Lee, Kwee Hyun Suh, Jeewoong Son. Discovery of HM61713 as an orally available and mutant EGFR selective inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-100. doi:10.1158/1538-7445.AM2014-LB-100