Download MendeleyDiscovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors.
De Clercq, D.J.H., Heppner, D.E., To, C., Jang, J., Park, E., Yun, C.H., Mushajiang, M., Shin, B.H., Gero, T.W., Scott, D.A., Janne, P.A., Eck, M.J., Gray, N.S.(2019) ACS Med Chem Lett 10: 1549-1553
- PubMed: 31749909
- DOI: https://doi.org/10.1021/acsmedchemlett.9b00381
- Primary Citation of Related Structures:
6P1D, 6P1L, 6P8Q - PubMed 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-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.
Organizational Affiliation:
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, United States.
