RAS protein–protein interfaces (RAS PPIs) (RAS PPIs)

RAS proteins (KRAS, HRAS, and NRAS) are small GTPases that function as molecular switches in signal transduction pathways controlling cell growth, differentiation, and survival (UniProt: P01116). Mutations in RAS genes are found in approximately 30% of all human cancers, making them high-priority therapeutic targets (PubMed: 31578472). Targeting RAS protein-protein interfaces (PPIs) involves the use of small molecules or biologics to disrupt the interaction between RAS and its regulatory proteins, such as the Guanine Nucleotide Exchange Factor (GEF) SOS1, or its downstream effectors like RAF, PI3K, and RALGEF (PubMed: 29967494). Historically, RAS was considered undruggable because it lacks deep, hydrophobic pockets suitable for small-molecule binding; however, the discovery of the Switch II pocket has enabled the development of inhibitors that lock RAS in an inactive state or sterically block PPIs (PubMed: 33479115). These therapies aim to shut down oncogenic signaling cascades in cancers such as pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (PubMed: 34108715). Current clinical candidates include SOS1 inhibitors that prevent RAS activation and RAS-multi inhibitors that target the conserved effector-binding interface across multiple RAS mutants (ClinicalTrials.gov: NCT04111458).

Other names

RAS-effector interactionsRAS-GEF interactionsRAS-SOS1 interfaceRAS-RAF interfaceRAS-PI3K interfaceRAS-effector binding domain

Disruption of the physical interaction between RAS GTPases and their upstream activators (GEFs) or downstream effectors (RAF, PI3K) to inhibit oncogenic signaling pathways.