Opportunities and Challenges of Small-Molecule Modulation of Protein-Protein Interactions

The complex networks formed by protein-protein interactions underpin a series of core biological processes, including signal transduction, cell proliferation, and DNA repair. Consequently, dysregulation of these interactions often serves as a driving factor in various human diseases. Targeting protein-protein interactions has opened a promising new avenue for drug discovery, and continued advances in this field hold great potential for achieving highly specific therapies against a wide range of complex diseases. The approval of PPI-targeting drugs has challenged the traditional view of such interfaces as "undruggable." In this review, we summarize several classic small-molecule PPI drugs that have been approved or have entered clinical trials, analyze the interfaces of target protein interactions, and elaborate on the opportunities presented by small-molecule modulation of PPIs. However, small molecules face considerable difficulties in targeting interactions involving transcription factors and other challenging targets, and molecular design remains hindered by obstacles such as the identification of lead compounds and poor pharmacokinetic properties.