Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 57, Issue 23, Pages 10176-10191Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm501578n
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Funding
- Office of Science, Office of Basic Energy Sciences of the U.S. Department of Energy [DE-AC02-05CH11231]
- National Institutes of Health, National Institute of General Medical Sciences
- Howard Hughes Medical Institute
- Michigan Economic Development Corp.
- Michigan Technology Tri-Corridor [085P1000817]
- U.S. DOE [DE-AC02-06CH11357]
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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.
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