Approaches to mitigate the risk of serious adverse reactions in covalent drug design

Covalent inhibition of target proteins using high affinity ligands bearing weakly electrophilic warheads is being adopted increasingly as design strategy in the discovery of novel therapeutics, and several covalent drugs have now received regulatory approval for indications in oncology. Experience to date with targeted covalent inhibitors has led to a number of design principles that underlie the safety and efficacy of this increasingly important class of molecules.

A review is provided of the current status of the covalent drug approach, emphasizing the unique benefits and attendant risks associated with reversible and irreversible binders. Areas of application beyond inhibition of tyrosine kinases are presented, and design considerations to de-risk covalent inhibitors with respect to undesirable off-target effects are discussed.

High selectivity for the intended protein target has emerged as a key consideration in mitigating safety risks associated with widespread proteome reactivity. Powerful chemical proteomics-based techniques are now available to assess selectivity in a drug discovery setting. Optimizing pharmacokinetics to capitalize on the intrinsically high potency of covalent drugs should lead to low daily doses and greater safety margins, while minimizing susceptibility to metabolic activation likewise will attenuate the risk of covalent drug toxicity.