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Talk by Matthias Gehringer

Title: "Covalent Inhibitors Targeting the Protein Kinases’ Cysteinome"
Occasion: SFB - Seminar
Start: 12.12.2023 - 16:15
Location: CellNanOs, 38/201

About the speaker: Jun.-Prof. Dr. Matthias Gehringer conducts research about medical chemistry and chemical biology in the Pharmaceutical Institut at the Eberhard Karls Universität Tübingen.

Abstract of the talk: Protein kinases are now among the major drug targets and around 80 small molecule inhibitors have entered the market since the groundbreaking approval of imatinib (Gleevec) in 2001. Covalent inhibitors, which have gained traction in recent years, have proven particularly useful in the protein kinase field due to their superior potency, selectivity, and prolonged duration of action. Of the >500 human protein kinases, almost half are characterized by the presence of an accessible, non-conserved cysteine residue in or around the ATP binding site, which can be targeted by mild electrophiles termed covalent "warheads". However, although ten covalent protein kinase inhibitors have now entered the market, only a small fraction of the protein kinases' "cysteinome" has been addressed so far. Moreover, the warhead chemistry used is mainly limited to attenuated Michael acceptors, most commonly α,β-unsaturated amides.

In my talk, I will highlight general properties, design principles, and available warhead chemistries for cysteine-targeted covalent protein kinase inhibitors. Moreover, I will present our recent efforts towards covalent inhibitors for protein kinases with a cysteine in different regions of the ATP binding pocket and I will showcase how canonical and non-canonical warhead chemistry can be harnessed to generate highly efficient and selective protein kinase inhibitors.