1. Targeting Her2-insYVMA with Covalent Inhibitors—A Focused Compound Screening and Structure-Based Design Approach
- Author
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Philip Klövekorn, Jonas Lategahn, Willem A. L. van Otterlo, Julia Hardick, Tobias Grabe, Daniel Rauh, Luke Hodson, Matthias P. Müller, Tonia Kirschner, Kirujan Jeyakumar, Matthias Baumann, Julia Ketzer, Sebastian Bauer, Susanne Terheyden, Janina Niggenaber, Christian Becker, Anke Unger, Hannah L. Tumbrink, Jörn Weisner, and Marina Keul
- Subjects
Models, Molecular ,Receptor, ErbB-2 ,Mutant ,Drug Evaluation, Preclinical ,Medizin ,01 natural sciences ,Structure-Activity Relationship ,03 medical and health sciences ,Western blot ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Structure–activity relationship ,Pyrroles ,Epidermal growth factor receptor ,Binding site ,Structural motif ,Protein Kinase Inhibitors ,030304 developmental biology ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,medicine.diagnostic_test ,biology ,Chemistry ,Receptor–ligand kinetics ,0104 chemical sciences ,Kinetics ,010404 medicinal & biomolecular chemistry ,Pyrimidines ,Biochemistry ,Drug Design ,biology.protein ,Molecular Medicine ,Cysteine - Abstract
Mutated or amplified Her2 serves as a driver of non-small cell lung cancer or mediates resistance toward the inhibition of its family member epidermal growth factor receptor with small-molecule inhibitors. To date, small-molecule inhibitors targeting Her2 which can be used in clinical routine are lacking, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds, which were applied against wild-type Her2 and its mutant variant Her2-A775_G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion parameters as well as mass spectrometry experiments and western blot analysis substantiated our approach.
- Published
- 2020
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