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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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