Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

Matthias Gehringer and Stefan A. Laufer
Journal of Medicinal Chemistry 
DOI: 10.1021/acs.jmedchem.8b01153

Targeted covalent inhibitors (TCIs) are designed to bind poorly conserved amino acids by means of reactive groups, the so-called warheads. Currently, targeting non-catalytic cysteine residues with acrylamides and other α,β-unsaturated carbonyl compounds is the predominant chemical strategy in TCI development. The recent ascent of covalent drugs has stimulated considerable efforts to characterize alternative warheads for the covalent-reversible and irreversible engagement of non-catalytic cysteine residues as well as other amino acids. This Perspective article provides an overview of warheads beyond α,β-unsaturated amides that were recently used in the design of targeted covalent ligands. Promising reactive groups that have not yet demonstrated their utility in TCI development are also highlighted. Special emphasis is placed on the discussion of reactivity and case studies illustrating applications in medicinal chemistry and chemical biology.