Load and lock: An emerging class of therapeutics that influence macromolecular dissociation

Biology is governed by macromolecular interactions, perturbation of which often lies at the heart of disease. Most therapeutic drugs, whether they are small molecules or biologics, exert their effects through impeding such interactions, whether they are of an enzyme with its substrate or a ligand with its receptor. Conversely, a handful of approved drugs and a larger number of candidates in development have the opposite effect: They either activate or inhibit a biological output by stabilizing a preexisting complex through reducing the rate at which its components dissociate (k_off). In this Review, we present examples of therapeutic candidates that we term “LOCKTACs,” which modulate k_off, and discuss possible theoretical and practical advantages of this class of drugs. Prospective discovery of LOCKTACs has the potential to usher in a new class of therapeutics for today’s most challenging targets.