Small-Molecule Stabilization of Protein-Protein Interactions: An Underestimated Concept in Drug Discovery?

The modulation of protein–protein interactions (PPIs) has been recognized as one of the most challenging tasks in drug discovery. While their systematic development has long been considered as intractable, this view has changed over the last years, with the first drug candidates undergoing clinical studies. To date, the vast majority of PPI modulators are interaction inhibitors. However, in many biological contexts a prolonged lifespan of a PPI might be desirable, calling for the complementary approach of PPI stabilization. In fact, nature offers impressive examples of this concept and some PPI‐stabilizing natural products have already found application as important drugs. Moreover, directed small‐molecule stabilization has recently been demonstrated. Therefore, it is time to take a closer look at the constructive side of modulating PPIs. Doing it the other way round: The modulation of protein–protein interactions (PPIs) by small molecules has become increasingly popular over the last few decades. However, “modulation” has mainly been perceived as “inhibition” of protein–protein interactions, omitting the complementary strategy of stabilizing such macromolecular complexes. This Minireview highlights amazing examples and the potential of this constructive side of modulating PPIs.