4RJ8
EGFR kinase (T790M/L858R) with inhibitor compound 8
Summary for 4RJ8
| Entry DOI | 10.2210/pdb4rj8/pdb |
| Related | 4RJ3 4RJ4 4RJ5 4RJ6 4RJ7 |
| Descriptor | Epidermal growth factor receptor, SULFATE ION, 1-cyclopentyl-N-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]-1H-pyrrolo[3,2-c]pyridin-6-amine, ... (4 entities in total) |
| Functional Keywords | protein kinase, phosphotransfer catalyst, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533 |
| Total number of polymer chains | 1 |
| Total formula weight | 38037.96 |
| Authors | Eigenbrot, C.,Yu, C. (deposition date: 2014-10-08, release date: 2014-11-26, Last modification date: 2023-09-20) |
| Primary citation | Hanan, E.J.,Eigenbrot, C.,Bryan, M.C.,Burdick, D.J.,Chan, B.K.,Chen, Y.,Dotson, J.,Heald, R.A.,Jackson, P.S.,La, H.,Lainchbury, M.D.,Malek, S.,Purkey, H.E.,Schaefer, G.,Schmidt, S.,Seward, E.M.,Sideris, S.,Tam, C.,Wang, S.,Yeap, S.K.,Yen, I.,Yin, J.,Yu, C.,Zilberleyb, I.,Heffron, T.P. Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation. J.Med.Chem., 57:10176-10191, 2014 Cited by PubMed Abstract: Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties. PubMed: 25383627DOI: 10.1021/jm501578n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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