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

The KRAS–PI3Kα interface is a critical protein-protein interaction (PPI) node where the GTP-bound KRAS oncoprotein binds to the Ras-binding domain (RBD) of the p110α catalytic subunit of phosphoinositide 3-kinase alpha (PI3Kα) (Gupta et al., Cell 2007). This interaction is essential for the oncogenic signaling that drives cell survival, proliferation, and metastasis in many KRAS-mutant cancers, including lung, colorectal, and pancreatic adenocarcinomas (Castellano et al., Cancer Cell 2013). Historically, targeting this interface was considered "undruggable" due to the weak nature of the interaction and structural challenges in resolving the complex. However, recent advances in chemoproteomics and structure-guided design have led to the discovery of "breaker" molecules like BBO-10203 and covalent inhibitors like VVD-669 that specifically disrupt this binding (Klebba et al., Science 2025). Unlike traditional PI3K inhibitors that block the ATP-binding catalytic site and cause systemic metabolic side effects like hyperglycemia, interface inhibitors selectively impair RAS-mediated activation while sparing homeostatic PI3K functions (Vividion Therapeutics, 2025). This approach aims to provide a wider therapeutic window and overcome resistance seen with KRAS or PI3K monotherapies.

Other names

KRAS-p110α interfaceRAS–PI3Kα interaction siteKRAS-RBD interfaceKRAS-PI3K complex

Allosteric or orthosteric inhibition of the protein-protein interaction between GTP-bound KRAS and the Ras-binding domain (RBD) of the p110α subunit of PI3Kα, preventing RAS-dependent kinase activation while sparing basal lipid kinase activity.