Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) RAS-binding domain (RBD) – RAS interface (PI3Kα RBD–RAS interface)

The Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) RAS-binding domain (RBD) – RAS interface is a critical regulatory site for the activation of the PI3Kα enzyme (UniProt P42336). PI3Kα is a lipid kinase that plays a central role in the PI3K/AKT/mTOR signaling pathway, which regulates cell growth, survival, and metabolism. The interaction between active, GTP-bound RAS proteins and the RBD of the p110α catalytic subunit facilitates the recruitment of PI3K to the plasma membrane, where it converts PIP2 to PIP3 (Fritsch et al., 2013). This interface is a significant therapeutic target because its disruption can selectively inhibit RAS-mediated PI3K activation, which is a driver in many cancers, including those with KRAS or PIK3CA mutations (Burke, 2018). Unlike traditional ATP-competitive inhibitors that target the kinase domain, drugs targeting this interface, such as the investigational RAS-mimetic Rigosertib, aim to block the physical protein-protein interaction (Athuluri-Divakar et al., 2016). Targeting this specific interface may offer a strategy to overcome resistance to conventional PI3K inhibitors or provide a more nuanced modulation of the pathway.

Other names

PIK3CA RBD-RAS interfacep110α-RAS interfacePI3K alpha RAS-binding domain

Inhibition of the protein-protein interaction (PPI) between the RAS-binding domain (RBD) of the p110α subunit and the effector-binding loop of RAS-GTP, thereby preventing the recruitment of PI3Kα to the plasma membrane and its subsequent activation (Athuluri-Divakar et al., 2016; Fritsch et al., 2013).