9JQ1

Crystal structure of EGFR T790M/C797S/L858R mutant in complex with 2,2-dichloro-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acetamide

This is a non-PDB format compatible entry.

Summary for 9JQ1

• Entry DOI: 10.2210/pdb9jq1/pdb
• Descriptor: Epidermal growth factor receptor, 2,2-bis(chloranyl)-~{N}-[5-[[5-chloranyl-4-[(2-dimethylphosphorylphenyl)amino]pyrimidin-2-yl]amino]-4-methoxy-2-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]ethanamide (3 entities in total)
• Functional Keywords: egfr, inhibitor, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38215.37

Authors

Wang, Y.,Ma, L.,Yang, X. (deposition date: 2024-09-27, release date: 2025-07-02, Last modification date: 2026-07-15)

Primary citation

Wang, Y.,Yu, Q.,Yang, X.,Ma, L.,Huang, R.,Chen, H.,Jiang, Z.,Wu, Z.,Wu, C.,Deng, X.,Wang, J.,Li, W.,He, Y.
A Dichloropropionamide-Substituted Diaminopyrimidine EGFR-TKI Overcomes Osimertinib Resistance in NSCLC via Dual Anchoring at Ser797 and Met793.
J.Med.Chem., 69:625-659, 2026

PubMed Abstract: The tertiary C797S mutation in the EGFR tyrosine kinase domain disrupts osimertinib binding, driving resistance in NSCLC. We designed a series of novel diaminopyrimidine derivatives to establish the interaction with Ser797. potently inhibited EGFR kinase with an IC of 3.86 nM (30-fold lower than osimertinib) and suppressed both double mutant NCI-H1975 and triple mutant H1975-M3 cells with ICs of 0.03 μM and 0.57 μM (14- and 11-fold reductions over osimertinib, respectively). Cocrystal X-ray analysis revealed that forms a "two-point tethering" in the ATP pocket with a hydrogen bond between its dichloropropionamide oxygen and Ser797, complemented by a hydrogen bond between terminal N of the piperazine ring and Phe795. Mechanistically, suppressed EGFR phosphorylation and downstream AKT, STAT3, and MAPK signaling, inhibiting proliferation, invasion, and migration. , achieved 71.15% tumor inhibition in H1975-M3 xenografts. This study identifies as a promising EGFR-TKI overcoming C797S-mediated resistance.

PubMed: 41428945
DOI: 10.1021/acs.jmedchem.5c02807

Experimental method

X-RAY DIFFRACTION (3.02 Å)