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Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors.

ABSTRACT: 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-11H-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 IC50 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.

SUBMITTER: De Clercq DJH

PROVIDER: S-EPMC6862338 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors.

De Clercq Dries J H DJH Heppner David E DE To Ciric C Jang Jaebong J Park Eunyoung E Yun Cai-Hong CH Mushajiang Mierzhati M Shin Bo Hee BH Gero Thomas W TW Scott David A DA Jänne Pasi A PA Eck Michael J MJ Gray Nathanael S NS

ACS medicinal chemistry letters 20191022 11

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-11H-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) mut ...[more]

PMID: 31749909

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