Julian Engel, André Richters, Matthäus Getlik, Stefano Tomassi, Marina Keul, Martin Termathe, Jonas Lategahn, Christian Becker, Svenja Mayer-Wrangowski, Christian Grütter, Niklas Uhlenbrock, Jasmin Krüll, Niklas Schaumann, Simone Eppmann, Patrick Kibies, Franziska Hoffgaard, Jochen Heil, Sascha Menninger, Sandra Ortiz-Cuaran, Johannes M Heuckmann, Verena Tinnefeld, René P Zahedi, Martin L Sos, Carsten Schultz-Fademrecht, Roman K Thomas, Stefan M Kast, Daniel Rauh
Receptor tyrosine kinases represent one of the prime targets in cancer therapy, as the dysregulation of these elementary transducers of extracellular signals, like the epidermal growth factor receptor (EGFR), contributes to the onset of cancer, such as non-small cell lung cancer (NSCLC). Strong efforts were directed to the development of irreversible inhibitors and led to compound CO-1686, which takes advantage of increased residence time at EGFR by alkylating Cys797 and thereby preventing toxic effects. Here, we present a structure-based approach, rationalized by subsequent computational analysis of conformational ligand ensembles in solution, to design novel and irreversible EGFR inhibitors based on a screening hit that was identified in a phenotype screen of 80 NSCLC cell lines against approximately 1500 compounds...
September 10, 2015: Journal of Medicinal Chemistry