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

The Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα) RAS-binding domain (RBD) is a critical structural motif within the p110α protein (encoded by PIK3CA) that mediates direct interaction with activated RAS GTPases (UniProt: P42336). This interaction is a fundamental step in the activation of the PI3K/AKT/mTOR signaling pathway, as it facilitates the recruitment of the PI3K complex to the plasma membrane in response to growth factor signaling (PMID: 7954826). In many human cancers, including breast, colorectal, and lung carcinomas, the RAS-PI3Kα interaction is constitutively enhanced by mutations in either RAS or PIK3CA, driving uncontrolled cell proliferation and survival (PMID: 17553925). While traditional PI3K inhibitors like Alpelisib target the ATP-binding pocket of the kinase domain, the RBD is an emerging therapeutic target for the development of protein-protein interaction (PPI) inhibitors (PMID: 28235898). By specifically blocking the RBD, researchers aim to disrupt the oncogenic synergy between RAS and PI3K, potentially offering a more selective therapeutic window and overcoming resistance to conventional kinase inhibitors. This approach is particularly relevant for treating RAS-mutant tumors where standard PI3K inhibition has shown limited clinical efficacy (PMID: 27161442).

Other names

PIK3CA RAS-binding domainp110α RBDPhosphoinositide 3-kinase alpha RBDPI3K alpha RBDp110-alpha RAS-binding domain

Disruption of the protein-protein interaction between RAS GTPases and the PI3Kα catalytic subunit to inhibit downstream AKT/mTOR signaling.