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-Ce

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• 作者：Gérald Lelais ; Robert Epple ; Thomas H. Marsilje ; Yun O. Long ; Matthew McNeill ; Bei Chen ; Wenshuo Lu ; Jaganmohan Anumolu ; Sangamesh Badiger ; Badry Bursulaya ; Michael DiDonato ; Rina Fong ; Jose Juarez ; Jie Li ; Mari Manuia ; Daniel E. Mason ; Perry Gordon ; Todd Groessl ; Kevin Johnson ; Yong Jia ; Shailaja Kasibhatla ; Chun Li ; John Isbell ; Glen Spraggon ; Steven Bender ; Pierre-Yves Michellys
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 28, 2016
• 年：2016
• 卷：59
• 期：14
• 页码：6671-6689
• 全文大小：753K
• 年卷期：0
• ISSN：1520-4804

文摘

Over the past 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 toward the discovery of 47 (EGF816, nazartinib), 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.