Design und Synthese hochselektiver chemischer Proteinkinase-Sonden und PROTACs durch kovalente Adressierung von Cysteinen in der Hinge-Region

01/01/2019 to 01/04/2022

Protein kinases are amongst the major drug targets of the 21st century. However, only a small fraction of the >518 human protein kinases has currently been addressed with selective inhibitors. For investigating the biological relevance of individual protein kinases, highly selective tool compounds ("chemical probes") are required. Due to the structural conservation of protein kinases, achieving selectivity is a major obstacle. Recently, the specific covalent targeting of non-catalytic cysteine residues has been employed as a successful strategy for the generation of kinase inhibitors with exquisite selectivity. In this project, a rare cysteine in the so-called hinge region will be exploited for the generation of specific irreversible ligands, covalent-reversible inhibitors and proteolysis targeting chimera (PROTACs). Together, these efforts aim to provide a comprehensive set of chemical probes to dissect catalytic and scaffolding/regulatory functions of the respective kinases. The obtained probes could facilitate the deconvolution of the kinases signaling pathways and serve as starting points for drug discovery endeavors.