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6HVE

Kinase domain of cSrc in complex with compound 9

Summary for 6HVE
Entry DOI10.2210/pdb6hve/pdb
DescriptorProto-oncogene tyrosine-protein kinase Src, ~{N}-[3-(4-methoxy-7~{H}-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]prop-2-enamide (3 entities in total)
Functional Keywordskinase inhibitor covalent inhibitor, transferase
Biological sourceGallus gallus (Chicken)
Total number of polymer chains2
Total formula weight66134.22
Authors
Keul, M.,Mueller, M.P.,Rauh, D. (deposition date: 2018-10-10, release date: 2019-10-23, Last modification date: 2024-11-13)
Primary citationLategahn, 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: 31857889
DOI: 10.1039/c9sc03445e
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.9 Å)
Structure validation

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数据于2025-07-16公开中

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