3IKA

Crystal Structure of EGFR 696-1022 T790M Mutant Covalently Binding to WZ4002

Summary for 3IKA

• Entry DOI: 10.2210/pdb3ika/pdb
• Related: 2jit 2jiu 2jiv
• Descriptor: Epidermal growth factor receptor, N-{3-[(5-chloro-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}prop-2-enamide (3 entities in total)
• Functional Keywords: egfr, t790m, wz4002, wz-4002, alternative splicing, atp-binding, cell membrane, disease mutation, disulfide bond, glycoprotein, isopeptide bond, kinase, membrane, nucleotide-binding, phosphoprotein, polymorphism, receptor, secreted, transferase, transmembrane, tumor suppressor, tyrosine-protein kinase, ubl conjugation
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 2
• Total formula weight: 75820.06

Authors

Yun, C.-H.,Eck, M.J. (deposition date: 2009-08-05, release date: 2010-01-12, Last modification date: 2024-11-27)

Primary citation

Zhou, W.,Ercan, D.,Chen, L.,Yun, C.H.,Li, D.,Capelletti, M.,Cortot, A.B.,Chirieac, L.,Iacob, R.E.,Padera, R.,Engen, J.R.,Wong, K.K.,Eck, M.J.,Gray, N.S.,Janne, P.A.
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.
Nature, 462:1070-1074, 2009

PubMed Abstract: The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.

PubMed: 20033049
DOI: 10.1038/nature08622

Experimental method

X-RAY DIFFRACTION (2.9 Å)