Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation [electronic resource].
- Washington, D.C. : United States. Dept. of Energy. Office of Basic Energy Sciences, 2014.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
- Physical Description:
- pages 10,176-10,191 : digital, PDF file
- Additional Creators:
- Argonne National Laboratory
United States. Department of Energy. Office of Basic Energy Sciences
National Institutes of Health (U.S.)
United States. Department of Energy. Office of Scientific and Technical Information
- 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. Here in this paper, 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.
- Published through SciTech Connect.
Journal of Medicinal Chemistry 57 23 ISSN 0022-2623 AM
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.
- Funding Information:
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