Discovery of EGF Receptor Inhibitors That Are Selective for the d746‐750/T790M/C797S Mutant through Structure‐Based de Novo Design
- 22 May 2017
- journal article
- research article
- Published by Wiley in Angewandte Chemie
- Vol. 129 (26) , 7742-7746
Abstract
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.Keywords
Funding Information
- Institute for Basic Science (IBS-R010-G1)
This publication has 22 references indexed in Scilit:
- EGFR C797S mutation mediates resistance to third-generation inhibitors in T790M-positive non-small cell lung cancerJournal of Hematology & Oncology, 2016
- Strategies to Overcome Acquired Resistances Conferred by Mutations in the Kinase Domain of EgfrFuture Medicinal Chemistry, 2016
- Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancerJournal of Hematology & Oncology, 2016
- Emerging Agents and New Mutations in EGFR-Mutant Lung CancerClinical Cancer Research, 2015
- Novel mutant-selective EGFR kinase inhibitors against EGFR T790MNature, 2009
- The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitorMolecular Cancer Therapeutics, 2008
- The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATPProceedings of the National Academy of Sciences, 2008
- Epidermal growth factor receptor mutations in lung cancerNature Reviews Cancer, 2007
- Erlotinib in Previously Treated Non–Small-Cell Lung CancerNew England Journal of Medicine, 2005
- EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib TherapyScience, 2004