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

Publication Type:

Journal Article

Source:

ACS Med Chem Lett, Volume 10, Issue 11, p.1549-1553 (2019)

Abstract:

<p>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-dibenzo[,][1,4]diazepin-11-one scaffold. Our structure-based medicinal chemistry effort yielded an inhibitor () of the EGFR(L858R/T790M) and EGFR(L858R/T790M/C797S) mutants with an IC of &sim;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.</p>

PDB: 
6P8Q, 6P1D, 6P1L
Detector: 
PILATUS
EIGER
Beamline: 
24-ID-C
24-ID-E