Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update.

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with a variety of new targeted covalent drugs having been approved in recent years. A key feature of such molecules is an intrinsically reactive group, typically a weak electrophile, which enables the irreversible or reversible formation of a covalent bond with a specific amino acid of the target protein. This reactive group, often called the "warhead", is a critical determinant of the ligand's activity, selectivity, and general biological properties. In 2019, we summarized emerging and re-emerging warhead chemistries to target cysteine and other amino acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 2019, 62, 5673-5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, the field has rapidly evolved. Here we discuss the progress on covalent warheads made since our last Perspective and their application in medicinal chemistry and chemical biology.

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

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.