Design of rigid protein-protein interaction inhibitors enables targeting of undruggable Mcl-1

Of the more than 120,000 protein-protein interactions (PPIs) in the human body, very few are directly modulated by FDA-approved small-molecule PPI inhibitors, highlighting a huge untapped opportunity for drug discovery. Here, we analyze the molecular mode of action of three recent breakthrough successes in the design of clinical-stage small-molecule PPI inhibitors, all of which inhibit the previously undruggable protein myeloid cell leukemia 1 (Mcl-1). We discovered that all the three clinical Mcl-1 inhibitors are rigidly prestructured free in solution and that the much larger Mcl-1 pries open to bind these small molecules. We suggest that small-molecule prestructuring could become a more general strategy for PPI inhibitor medicines and point out methods how synthetic chemists can build in such molecular rigidity.