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 (R,E)-N-(7-Chloro-1-(1-[4-(dimethylamino)but-2-enoyl]azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide (EGF816), a Novel, Potent and WT Sparing Covalent Inhibitor of Oncogenic (L858R, ex19del) and Resistant (T790M) EGFR Mutants for the Treatment of EGFR Mutant Non-Small Cell Lung Cancers. Journal of Medicinal Chemistry, 59 (14). pp. 6671-6689. ISSN 10.1021/acs.jmedchem.5b01985

Abstract

Over the last decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach towards the discovery of 47 (EGF816), 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 47 as the clinical candidate.

Item Type:	Article
Date Deposited:	09 Nov 2016 00:45
Last Modified:	09 Nov 2016 00:45
URI:	https://oak.novartis.com/id/eprint/28634