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

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) is a critical lipid kinase in the PI3K/AKT/mTOR pathway, which governs essential cellular processes such as growth, proliferation, and survival (UniProt P42336). The RAS-binding interface, located within the p110α subunit, serves as a vital regulatory site where activated RAS proteins bind to trigger PI3K signaling (PubMed 30104378). This interaction is a major driver in many human cancers, particularly those with co-occurring mutations in RAS and PIK3CA. Targeting this specific interface represents an innovative therapeutic approach aimed at disrupting the protein-protein interaction (PPI) between RAS and PI3Kα, potentially offering greater selectivity than traditional ATP-competitive inhibitors. While most clinical PI3K inhibitors like Alpelisib target the catalytic site, agents like Rigosertib have been investigated for their ability to act as RAS mimetics that interfere with the RAS-binding domain (PubMed 27261569). Successfully inhibiting this interface could provide a means to overcome resistance mechanisms and reduce the systemic toxicities, such as hyperglycemia, often associated with broad PI3K inhibition.

Other names

PIK3CA RAS-binding domainp110α RBDPI3K alpha-RAS interfacePhosphoinositide-3-kinase catalytic subunit alpha RAS-binding domain

Disruption of the protein-protein interaction between RAS and the PI3Kα RAS-binding domain (RBD), preventing RAS-mediated recruitment and activation of PI3Kα at the plasma membrane.