RAS–Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha protein–protein interaction (RAS–PI3Kα PPI)

The RAS–PI3Kα protein–protein interaction is a critical node in oncogenic signaling, where activated RAS (typically KRAS, HRAS, or NRAS) binds to the Ras-binding domain (RBD) of the p110α catalytic subunit of Phosphatidylinositol 3-kinase (PI3Kα) (PMID: 21460850). This interaction facilitates the recruitment of PI3Kα to the plasma membrane, leading to the production of PIP3 and subsequent activation of the AKT/mTOR pathway, which drives cell growth, survival, and metabolism (PMID: 17640892). In many cancers, particularly those with KRAS or PIK3CA mutations, this interaction is constitutively active, making it a high-priority therapeutic target (PMID: 29056346). Unlike traditional kinase inhibitors that target the ATP-binding pocket of PI3Kα, PPI inhibitors aim to disrupt the physical association between RAS and PI3Kα. This approach potentially offers greater specificity and may overcome resistance mechanisms associated with catalytic site mutations. Therapeutic candidates like Rigosertib have been investigated for their ability to act as RAS mimetics, blocking the interaction with multiple effectors including PI3Kα (PMID: 27153498). However, achieving high affinity and selectivity for this flat protein interface remains a significant medicinal chemistry challenge.

Other names

RAS-p110α interactionRAS-PIK3CA interactionRAS-PI3K signaling complexRAS-PI3K interface

Disruption of the physical binding between RAS-GTP and the Ras-binding domain (RBD) of the p110α subunit of PI3K, preventing its recruitment to the plasma membrane and subsequent activation.