Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors.
作者： Dries J. H. De Clercq , David E. Heppner , Ciric To , Jaebong Jang , Eunyoung Park
DOI: 10.1021/ACSMEDCHEMLETT.9B00381
关键词:
摘要: 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 comprising 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one scaffold. Our structure-based medicinal chemistry effort yielded an inhibitor (3) EGFR(L858R/T790M) EGFR(L858R/T790M/C797S) mutants with IC50 ∼10 nM high selectivity, as assessed by kinome profiling. Further efforts to develop dibenzodiazepinone may serve basis options drug-resistant mutations.
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