6S8A
Crystal Structure of EGFR-T790M/C797S in Complex with Covalent Pyrrolopyrimidine 19h
Summary for 6S8A
| Entry DOI | 10.2210/pdb6s8a/pdb |
| Descriptor | Epidermal growth factor receptor, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ~{N}-[3-[6-[4-(4-methylpiperazin-1-yl)phenyl]-4-(2-methylpropoxy)-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl]propanamide, ... (4 entities in total) |
| Functional Keywords | egfr, t790m/c797s, covalent pyrrolopyrimide, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38423.50 |
| Authors | Niggenaber, J.,Mueller, M.P.,Rauh, D. (deposition date: 2019-07-09, release date: 2019-10-16, Last modification date: 2024-01-24) |
| Primary citation | Lategahn, J.,Keul, M.,Klovekorn, P.,Tumbrink, H.L.,Niggenaber, J.,Muller, M.P.,Hodson, L.,Flasshoff, M.,Hardick, J.,Grabe, T.,Engel, J.,Schultz-Fademrecht, C.,Baumann, M.,Ketzer, J.,Muhlenberg, T.,Hiller, W.,Gunther, G.,Unger, A.,Muller, H.,Heimsoeth, A.,Golz, C.,Blank-Landeshammer, B.,Kollipara, L.,Zahedi, R.P.,Strohmann, C.,Hengstler, J.G.,van Otterlo, W.A.L.,Bauer, S.,Rauh, D. Inhibition of osimertinib-resistant epidermal growth factor receptor EGFR-T790M/C797S. Chem Sci, 10:10789-10801, 2019 Cited by PubMed Abstract: Precision medicine has revolutionized the treatment of patients in EGFR driven non-small cell lung cancer (NSCLC). Targeted drugs show high response rates in genetically defined subsets of cancer patients and markedly increase their progression-free survival as compared to conventional chemotherapy. However, recurrent acquired drug resistance limits the success of targeted drugs in long-term treatment and requires the constant development of novel efficient inhibitors of drug resistant cancer subtypes. Herein, we present covalent inhibitors of the drug resistant gatekeeper mutant EGFR-L858R/T790M based on the pyrrolopyrimidine scaffold. Biochemical and cellular characterization, as well as kinase selectivity profiling and western blot analysis, substantiate our approach. Moreover, the developed compounds possess high activity against multi drug resistant EGFR-L858R/T790M/C797S in biochemical assays due to their highly reversible binding character, that was revealed by characterization of the binding kinetics. In addition, we present the first X-ray crystal structures of covalent inhibitors in complex with C797S-mutated EGFR which provide detailed insight into their binding mode. PubMed: 31857889DOI: 10.1039/c9sc03445e PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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