Insight into the Inhibition of Drug‐Resistant Mutants of the Receptor Tyrosine Kinase EGFR. Issue 36 (5th August 2016)

• Record Type: Journal Article
• Authors: Engel, Julian; Becker, Christian; Lategahn, Jonas; Keul, Marina; Ketzer, Julia; Mühlenberg, Thomas; Kollipara, Laxmikanth; Schultz‐Fademrecht, Carsten; Zahedi, René P.; Bauer, Sebastian; Rauh, Daniel
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 36(2016)
• Page Start: 10909
• Page End: 10912
• Publication Date: 2016-08-05
• Subjects: cancer -- drug discovery -- drug resistance -- medicinal chemistry -- structure-based drug design; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201605011
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : Methods against mutants : Targeting acquired drug resistance represents the major challenge in the treatment of EGFR‐driven non‐small‐cell lung cancer. Complex crystal structures of new covalent inhibitors and detailed kinetic studies provide insight into the key features required for targeting EGFR mutations, including EGFR‐L858R/T790M/C797S.