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Insight into the Inhibition of Drug‐Resistant Mutants of the Receptor Tyrosine Kinase EGFR |
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| Authors: | M?Sc Julian Engel M?Sc Christian Becker M?Sc Jonas Lategahn M?Sc Marina Keul Julia Ketzer Dr Thomas Mühlenberg M?Sc Laxmikanth Kollipara Dr Carsten Schultz‐Fademrecht Dr René P Zahedi Prof?Dr Sebastian Bauer Prof?Dr Daniel Rauh |
| Affiliation: | 1. Technische Universit?t Dortmund, Fakult?t für Chemie und Chemische Biologie, Dortmund, Germany;2. Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany;3. German Cancer Consortium (DKTK), Heidelberg, Germany;4. Leibnitz-Institut für Analytische Wissenschaften—ISAS—e.V., Dortmund, Germany;5. Lead Discovery Center, Dortmund, Germany |
| 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. |
| Keywords: | cancer drug discovery drug resistance medicinal chemistry structure-based drug design |
