Advances in Covalent Drug Discovery Technologies

From Aspirin to Targeting KRAS: These Technologies Are Redrawing the Frontiers of Drug Discovery

From aspirin to modern KRAS inhibitors, covalent drugs have evolved from chance discoveries into rationally designed therapeutics. Once approached cautiously because of potential off-target effects, they are now helping researchers pursue targets previously considered undruggable.

This progress has been supported by advances in covalent screening. WuXi Biology’s covalent DNA-encoded library (cDEL) platform extends the search beyond cysteine to other amino acid residues. Two complementary approaches, covalent high-throughput screening (cHTS) and covalent fragment-based drug discovery (cFBDD), provide additional paths for identifying and optimizing covalent binders.

In this article, we highlight a study with ETH Zurich that evaluated 59 electrophilic warheads for DEL applications. Of these, 21 combined high coupling yield, strong reactivity, and high stability. These findings can help guide the design of future covalent libraries.