5J9Y

EGFR-T790M in complex with pyrazolopyrimidine inhibitor 1b

Summary for 5J9Y

• Entry DOI: 10.2210/pdb5j9y/pdb
• Descriptor: Epidermal growth factor receptor, (R)-1-(3-(4-amino-3-(naphthalen-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (3 entities in total)
• Functional Keywords: tyrosine kinase, covalent inhibitor, drug resistance, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 37362.32

Authors

Becker, C.,Engel, J.,Rauh, D. (deposition date: 2016-04-11, release date: 2016-08-17, Last modification date: 2016-09-07)

Primary citation

Engel, J.,Becker, C.,Lategahn, J.,Keul, M.,Ketzer, J.,Muhlenberg, T.,Kollipara, L.,Schultz-Fademrecht, C.,Zahedi, R.P.,Bauer, S.,Rauh, D.
Insight into the Inhibition of Drug-Resistant Mutants of the Receptor Tyrosine Kinase EGFR.
Angew.Chem.Int.Ed.Engl., 55:10909-10912, 2016

PubMed Abstract: Targeting acquired drug resistance represents the major challenge in the treatment of EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we describe the structure-based design, synthesis, and biological evaluation of a novel class of covalent EGFR inhibitors that exhibit excellent inhibition of EGFR-mutant drug-resistant cells. Protein X-ray crystallography combined with detailed kinetic studies led to a deeper understanding of the mode of inhibition of EGFR-T790M and provided insight into the key principles for effective inhibition of the recently discovered tertiary mutation at EGFR-C797S.

PubMed: 27496389
DOI: 10.1002/anie.201605011

Experimental method

X-RAY DIFFRACTION (2.8 Å)