Thursday, July 2, 2020

Covalent Kinase Inhibitors: An Overview

Gehringer M. (2020) Covalent Kinase Inhibitors: An Overview. In: Topics in Medicinal Chemistry. Springer, Berlin, Heidelberg

Covalent targeting has experienced a revival in the last decade, especially in the area of protein kinase inhibitor development. Generally, covalent inhibitors make use of an electrophilic moiety often termed “warhead” to react with a nucleophilic amino acid, most frequently a cysteine. High efficacy and excellent selectivity in the kinome have been achieved by addressing poorly conserved, non-catalytic cysteine residues with so-called targeted covalent inhibitors (TCIs). Despite the challenges associated with covalent modifiers, application of the TCI approach for the discovery of new treatments has been very successful with six covalent kinase inhibitors having gained approval in the last few years. A multitude of reactive chemical probes and tool compounds has further been developed. Beside cysteine, other nucleophilic amino acids including tyrosine and lysine have also been addressed with suitable electrophiles and covalent-reversible chemistry has recently complemented our toolbox for designing covalent kinase inhibitors. Covalent ligands have also been used in the framework of chemical-genetics approaches or to tackle allosteric pockets, which are often difficult to address.

This chapter aims at providing a general introduction to covalent kinase inhibitors and an overview of the current state of research highlighting major targeting strategies, developments, and advances in this field. More detailed information on certain targets and approaches can be found in dedicated chapters of this book.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

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