28/08/2025
Load and lock: An emerging class of therapeutics that influence macromolecular dissociation …
molecules that reduce the dissociation rate (koff) for biomolecular complexes and explain how this mechanism offers a powerful way to redirect endogenous interactions for therapeutic benefit. They named the molecules that reduce koff LOCKTACs and provide examples of emerging areas for preclinical research. —Michael A. Funk
We define LOCKTACs as compounds that reduce the koff of naturally interacting molecules, effectively “locking” a dynamic complex in place. Like proteolysis-targeting molecular chimeras (PROTACs) or molecular glues, a LOCKTAC has two binding surfaces that tether two partners together. However, instead of forging a new protein-protein interaction, LOCKTACs stabilize a preexisting, functionally relevant interaction to make it last longer. These can be small or large molecules that bind at, adjacent to, or even at a distance from the interface of the target complex to form a more persistent assembly.
LOCKTACs can either enhance or inhibit a biological function, depending on which interaction is stabilized. Activator LOCKTACs stabilize transient or inefficient complexes that promote a process, thereby boosting that process. For example, risdiplam is used in the treatment of spinal muscular atrophy and works by altering splicing of the SMN2 mRNA through stabilizing its binding to U1 small nuclear ribonucleoprotein. By contrast, inhibitory LOCKTACs hold together interactions that normally need to fall apart, thereby blocking a process. For example, sovilnesib can stop the kinesin KIF18A molecular motor from moving along microtubules by preventing the necessary bind-and-release catalytic cycle. In both cases, the drug forces a normally short-lived interaction to persist, which can either enhance or disrupt the targeted pathway, depending on the biological context.
OUTLOOK
LOCKTACs are promising because they open new avenues to modulate disease mechanisms. By reinforcing an existing interaction rather than blocking one, a LOCKTAC can target less-conserved surfaces and avoid competing with high-affinity natural ligands. This may provoke fewer off-target effects and enable drugging of targets once considered out of reach.
The discovery of LOCKTACs poses challenges. Because locking an interaction can result in agonism or antagonism depending upon context, targets will need to be selected judiciously. Moreover, screening for slow dissociation requires time-resolved kinetic assays that are more difficult than standard binding tests. Nevertheless, LOCKTACs represent a promising, largely untapped opportunity to develop drugs against difficult targets. By drawing attention to a diverse set of existing and emerging drugs that work through a LOCKTAC-like mechanism, we seek to inspire deliberate efforts to unlock a new chapter in pharmacology through the pursuit of “sustained proximity.”
Cells navigate through complex environments and solve mazes by creating their own chemotactic gradients.
