Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation

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• 作者：Emily J. Hanan ; Charles Eigenbrot ; Marian C. Bryan ; Daniel J. Burdick ; Bryan K. Chan ; Yuan Chen ; Jennafer Dotson ; Robert A. Heald ; Philip S. Jackson ; Hank La ; Michael D. Lainchbury ; Shiva Malek ; Hans E. Purkey ; Gabriele Schaefer ; Stephen Schmidt ; Eileen M. Seward ; Steve Sideris ; Christine Tam ; Shumei Wang ; Siew Kuen Yeap ; Ivana Yen ; Jianping Yin ; Christine Yu ; Inna Zilberleyb ; Timothy P. Heffron
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：10176-10191
• 全文大小：707K
• ISSN：1520-4804

文摘

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.