Son of Sevenless homolog 1 - Kirsten rat sarcoma virus oncogene homolog protein-protein interaction interface (SOS1-KRAS PPI) (SOS1-KRAS PPI)

The SOS1-KRAS protein-protein interaction interface is a critical regulatory node in the RAS/MAPK signaling pathway (UniProt Q07889, P01116). SOS1 (Son of Sevenless homolog 1) functions as a guanine nucleotide exchange factor (GEF) that catalyzes the exchange of GDP for GTP on KRAS, thereby switching KRAS from an inactive to an active signaling state (PubMed: 32814534). This interaction is essential for the activation of both wild-type and various oncogenic mutant forms of KRAS, which drive approximately 25% of human cancers, including lung, colorectal, and pancreatic malignancies (PubMed: 31811050). Therapeutic targeting of this interface involves small molecules that bind to SOS1, disrupting its ability to engage KRAS and effectively "locking" KRAS in its inactive, GDP-bound form (PubMed: 31811050). This strategy is being explored as a monotherapy and in combination with direct KRAS inhibitors (e.g., G12C inhibitors) to prevent adaptive resistance and enhance clinical efficacy (ClinicalTrials.gov: NCT04111458).

Other names

SOS1-KRAS interaction interfaceSOS1-RAS interfaceSOS1-KRAS complexSOS1:KRAS interface

Inhibition of the SOS1-KRAS protein-protein interaction by small molecules that bind to the catalytic or allosteric sites of SOS1, preventing the nucleotide exchange of GDP for GTP and maintaining KRAS in its inactive state (PubMed: 31811050).