7VRE
The crystal structure of EGFR T790M/C797S with the inhibitor HCD2892
Summary for 7VRE
| Entry DOI | 10.2210/pdb7vre/pdb |
| Descriptor | Epidermal growth factor receptor, 5-chloranyl-N-[5-chloranyl-2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-(1-ethylsulfonylindol-3-yl)pyrimidin-2-amine (3 entities in total) |
| Functional Keywords | egfr, inhibitor, complex, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38119.00 |
| Authors | Zhu, S.J. (deposition date: 2021-10-22, release date: 2022-06-08, Last modification date: 2023-11-29) |
| Primary citation | Chen, H.,Lai, M.,Zhang, T.,Chen, Y.,Tong, L.,Zhu, S.,Zhou, Y.,Ren, X.,Ding, J.,Xie, H.,Lu, X.,Ding, K. Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations. J.Med.Chem., 65:6840-6858, 2022 Cited by PubMed Abstract: Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5'-triphosphate-competitive or allosteric EGFR inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFR inhibitors by using a macrocyclization strategy. Representative compound potently inhibited EGFR and EGFR mutants with IC values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFR and Ba/F3-EGFR cells with IC values of 0.036 and 0.052 μM, respectively, which is 10-20-fold more potent than brigatinib. also potently inhibited the EGFR-mutated PC-9-OR NSCLC cell proliferation with an IC value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFR-mediated resistance in NSCLC patients. PubMed: 35446588DOI: 10.1021/acs.jmedchem.2c00168 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.507 Å) |
Structure validation
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