Disease-relevant transient protein-protein interfaces in oncology (PPI)

Disease-relevant transient protein-protein interfaces (PPIs) in oncology are dynamic, reversible physical associations between proteins that drive malignant transformation and cancer progression (Scott et al., 2016, Nature Reviews Drug Discovery). These interfaces are central to critical cellular processes such as signal transduction, DNA repair, and the regulation of apoptosis (Lu et al., 2020, Signal Transduction and Targeted Therapy). Unlike stable protein complexes, transient PPIs form and dissociate in response to specific cellular signals, making them highly sensitive regulators of cell fate. Historically, these surfaces were deemed "undruggable" because they are typically large and flat, lacking the well-defined pockets found in enzymes (Arkin et al., 2014, Chemistry & Biology). However, the development of small molecules like Venetoclax, which disrupts the Bcl-2/Bax interface, has proven that these sites can be successfully targeted to induce cancer cell death. Current therapeutic strategies focus on using peptidomimetics or fragment-based discovery to identify molecules that can wedge into these interfaces with high specificity. The primary goal of targeting these PPIs is to selectively inhibit oncogenic signaling or reactivate tumor suppressors like p53. Despite their potential, challenges remain regarding the delivery of these often large inhibitors and the risk of disrupting essential physiological interactions in non-cancerous cells.

Other names

Transient PPIsDynamic protein-protein interactionsOncogenic protein-protein interfaces

Competitive inhibition of protein-protein binding surfaces to prevent the formation of functional signaling complexes or to displace natural ligands and inhibitors.