Lelais, Gerald, Epple, Robert, Marsilje, Thomas, Long, Yun, Mcneill, Matthew, Chen, Bei, Lu, Wenshuo, Anumolu, Jaganmohan, Badiger, Sangamesh, Bursulaya, Badry, Didonato, Michael, Fong, Rina, Juarez, Jose, Li, Jie, Manuia, Mari, Mason, Daniel, Gordon, William, Groessl, Todd, Johnson, Kevin, Jia, Yong, Kasibhatla, Shailaja, Li, Chun, Isbell, John, Spraggon, Glen, Bender, Steven and Michellys, Pierre (2016) Discovery of a Novel and Potent Mutant Selective EGFR Inhibitor (EGF816) for the Treatment of EGFR mutant Non-Small Cell Lung Cancers. Journal of Medicinal Chemistry. ISSN 0022-26231520-4804

Abstract

In the last decade, major advances in the treatment of EGFR mutant lung cancers have been achieved. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition remain a challenge and new therapies are urgently needed. Herein, we describe our approach towards the discovery of EGF816 (18), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 18 as the clinical candidate.

Item Type:	Article
Date Deposited:	27 Jul 2016 00:45
Last Modified:	27 Jul 2016 00:45
URI:	https://oak.novartis.com/id/eprint/27796