Never Gonna Give You Up – Current Developments in Covalent Protein Kinase Inhibitors

Laura Hillebrand; Matthias Gehringer

doi:10.2533/chimia.2022.435

Never Gonna Give You Up – Current Developments in Covalent Protein Kinase Inhibitors

Authors

Laura Hillebrand aDepartment of Pharmaceutical & Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany
Matthias Gehringer Department of Pharmaceutical & Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) ‘Image-Guided & Functionally Instructed Tumor Therapies’, University of Tübingen, 72076 Tübingen, Germany

DOI:

https://doi.org/10.2533/chimia.2022.435

Keywords:

Covalent inhibitors, Cysteine targeting, Protein kinases

Abstract

Covalent inhibitors have recently seen a revival in medicinal chemistry. Inhibitors addressing non-catalytic cysteine residues with weakly reactive electrophiles have been very successfully employed to target protein kinases, one of the major druggable protein families. Here we provide an overview of irreversible and reversible covalent protein kinase inhibitors in clinical development and beyond. We further spotlight recent advances in targeting amino acids other than cysteine and the reactive groups utilized in covalent protein kinase inhibitors.