RAS pathway protein-protein interfaces (RAS PPIs)

RAS pathway protein-protein interfaces (PPIs) are the physical contact surfaces between RAS family GTPases (KRAS, HRAS, and NRAS) and their upstream activators or downstream effectors (UniProt P01116, P01112, P01111). These interfaces are essential for transmitting signals that govern fundamental cellular processes such as proliferation, differentiation, and survival via the MAPK and PI3K pathways (NIH/NCBI). In oncogenic states, mutated RAS proteins constitutively interact with effectors like RAF kinases and PI3K, leading to persistent signaling and tumor growth (Nature Reviews Drug Discovery, 2020). Historically labeled "undruggable" due to the lack of traditional small-molecule binding pockets, RAS is now being targeted through the disruption of these PPIs. Therapeutic strategies include using small molecules to block the RAS-SOS1 interaction to prevent RAS activation (Boehringer Ingelheim, 2023) or employing tri-complex inhibitors that sterically hinder RAS-effector binding (Revolution Medicines, 2023). These approaches aim to provide high specificity for mutant RAS signaling while minimizing the impact on normal cellular functions.

Other names

RAS-effector interactionsRAS-regulator interfacesRAS-RAF interfaceRAS-SOS1 interfaceRAS-PI3K interfaceRAS-GEF interface

Inhibition of protein-protein interactions between RAS and its effectors (e.g., RAF, PI3K) or regulators (e.g., SOS1) through orthosteric blockade, allosteric modulation, or the formation of inhibitory tri-complexes.