Disrupting the Undruggable: Emerging Modalities for Targeting Protein–Protein Interactions in Oncology

Protein-protein interactions (PPIs) are critical for cellular signaling, apoptosis regulation, and immune function in the body, and dysregulation is a hallmark of cancer. The large, dynamic, and shallow nature of PPI interfaces rendered them "undruggable" by conventional small molecules in the past. Recent advances in structural biology, chemical innovation, and artificial intelligence have revolutionized the landscape of PPI-directed drug discovery. This review summarizes the mechanistic roles of PPIs in oncogenesis, critically discusses novel therapeutic interventions, such as small molecules, peptidomimetics, stapled peptides, proteolysis-targeting chimeras (PROTACs), molecular glues, and AI-based drug optimization strategies, altering the druggable proteome in oncology. Therapeutics with clinically well-validated action, including Venetoclax and AMG 510, and next-generation candidates demonstrate the translational applications of these approaches. Some of the key challenges, such as interface complexity, specificity, bioavailability, and resistance, are addressed together with countermeasures like rational design, combination therapies, enhanced delivery systems, and biomarker-based patient selection. To this end, the incorporation of multi-omics data and artificial-intelligence (AI)-driven modeling technologies is revolutionizing the personalized cancer therapeutics development space. Collectively, these advances mark a paradigm shift: PPIs, once considered inaccessible, are now at the forefront of precision oncology, offering new hope for patients with previously intractable malignancies.