6P1D
Crystal structure of EGFR with mutant-selective dihydrodibenzodiazepinone allosteric inhibitor
Summary for 6P1D
| Entry DOI | 10.2210/pdb6p1d/pdb |
| Descriptor | Epidermal growth factor receptor, 10-benzyl-8-fluoro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total) |
| Functional Keywords | egfr, cancer, inhibitor, signaling protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 152646.18 |
| Authors | Heppner, D.E.,Eck, M.J. (deposition date: 2019-05-19, release date: 2019-12-18, Last modification date: 2023-10-11) |
| Primary citation | 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. Discovery and Optimization of Dibenzodiazepinones as Allosteric Mutant-Selective EGFR Inhibitors. Acs Med.Chem.Lett., 10:1549-1553, 2019 Cited by 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-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 ∼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. PubMed: 31749909DOI: 10.1021/acsmedchemlett.9b00381 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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