RAS–Phosphoinositide 3-kinase alpha interface (RAS–PI3Kα interface) (RAS–PI3Kα interface)

The RAS–Phosphoinositide 3-kinase alpha interface (RAS–PI3Kα interface) is a critical protein-protein interaction (PPI) site where active, GTP-bound RAS proteins (such as KRAS, HRAS, and NRAS) bind to the Ras-binding domain (RBD) of the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K) (Source: UniProt P42336; PubMed: 30333627). This interaction is a fundamental step in the activation of the PI3K/AKT/mTOR signaling pathway, which regulates essential cellular processes including growth, proliferation, and survival (Source: Nature Reviews Cancer, 2021). In many cancers, particularly those driven by KRAS mutations, this interface is constitutively active or hyper-responsive, making it a high-priority target for therapeutic intervention (Source: PubMed: 31548604). Unlike traditional kinase inhibitors that target the ATP-binding pocket of PI3K, drugs targeting this interface aim to disrupt the physical association between RAS and PI3K, thereby preventing the recruitment of PI3K to the plasma membrane (Source: Nature, 2023). This approach potentially offers greater selectivity and reduced toxicity compared to broad PI3K inhibition. Current drug development efforts focus on small molecules and "RAS(ON)" inhibitors, such as RMC-6236, that stabilize the inactive state or block effector binding, with several candidates in early-stage clinical trials for KRAS-mutant solid tumors (Source: Revolution Medicines Pipeline). Success in targeting this interface represents a significant shift from inhibiting enzymatic activity to modulating the spatial organization of oncogenic signaling complexes.

Other names

RAS-PI3K interactionRAS-p110α interfaceRAS-binding domain of PI3KαKRAS-PI3Kα interfaceRAS-PIK3CA interaction

Inhibition of the protein-protein interaction (PPI) between active, GTP-bound RAS proteins and the Ras-binding domain (RBD) of the p110α catalytic subunit of PI3K, preventing PI3K recruitment to the plasma membrane and subsequent AKT pathway activation.