Open AccessDiscovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors
Author(s) -
Dries J.H. De Clercq,
David E. Heppner,
Ciric To,
Jaebong Jang,
EunYoung Park,
CaiHong Yun,
Mierzhati Mushajiang,
Bo Hee Shin,
Thomas W. Gero,
David A. Scott,
Pasi A. Jänne,
Michael J. Eck,
Nathanael S. Gray
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00381
Subject(s) - kinome , t790m , allosteric regulation , mutant , egfr inhibitors , drug discovery , chemistry , kinase , computational biology , osimertinib , epidermal growth factor receptor , cancer research , erlotinib , biochemistry , biology , enzyme , gefitinib , receptor , gene
Allosteric kinase inhibitors represent a promising new therapeutic strategy for targeting kinases harboring oncogenic driver mutations in cancers. Here, we report the discovery, optimization, and structural characterization of allosteric mutant-selective EGFR inhibitors comprising a 5,10-dihydro-11 H -dibenzo[ b , e ][1,4]diazepin-11-one scaffold. Our structure-based medicinal chemistry effort yielded an inhibitor ( 3 ) of the EGFR(L858R/T790M) and EGFR(L858R/T790M/C797S) mutants with an IC 50 of ∼10 nM and high selectivity, as assessed by kinome profiling. Further efforts to develop allosteric dibenzodiazepinone inhibitors may serve as the basis for new therapeutic options for targeting drug-resistant EGFR mutations.