Oncogenic protein-protein interaction (PPI) (PPI)

Oncogenic protein-protein interactions (PPIs) are physical associations between proteins that facilitate the initiation, progression, and survival of cancer cells. These interactions mediate critical signaling cascades, such as the MAPK/ERK and PI3K/AKT pathways, and regulate the balance between pro-apoptotic and anti-apoptotic signals (Scott et al., 2016, Nature Reviews Drug Discovery). In many cancers, PPIs are altered through protein overexpression or mutations that stabilize oncogenic complexes, such as the MDM2-p53 or BCL2-BAX interfaces (Nero et al., 2014, Nature Reviews Cancer). While PPIs were traditionally viewed as difficult to target with small molecules due to their large and relatively flat contact surfaces, modern drug discovery techniques like fragment-based screening and macrocycles have successfully produced clinical-grade inhibitors (Ran & Gestwicki, 2018, Journal of Medicinal Chemistry). Therapeutic strategies often focus on competitive inhibition at the hot spots of the interface to disrupt the assembly of functional complexes (Souers et al., 2013, Nature Medicine). Consequently, targeting PPIs has emerged as a powerful approach to modulate pathways previously considered undruggable in oncology.

Other names

Protein-protein interactionOncogenic PPIProtein-protein interfacePPI inhibitionProtein-protein interaction network

Drugs targeting oncogenic PPIs typically act as orthosteric inhibitors that bind to hot spots on the protein interface, thereby preventing the formation of functional complexes necessary for oncogenic signaling or the inhibition of apoptosis (Scott et al., 2016). Some agents may also act allosterically by binding to a site distant from the interface and inducing a conformational change that disrupts the interaction (Nero et al., 2014).