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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 |