Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 26, Pages 7634-7638Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201703389
Keywords
EGFR; inhibitors; kinases; drug discovery; structure-based design
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Funding
- Institute for Basic Science [IBS-R010-G1]
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Next-generation epidermal growth factor receptor (EGFR) inhibitors against the d746-750/T790M/C797S mutation were discovered through two-track virtual screening and de novo design. A number of nanomolar inhibitors were identified using 2-aryl-4-aminoquinazoline as the molecular core and the modified binding energy function involving a proper dehydration term, which provides important structural insight into the key principles for high inhibitory activities against the d746-750/T790M/C797S mutant. Furthermore, some of these EGFR inhibitors showed a greater than 1000-fold selectivity for the d746-750/T790M/C797S mutant over the wild type, as well as nanomolar activity against the mutant.
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