Son of sevenless homolog 1 (SOS1)–KRAS protein-protein interface (SOS1–KRAS interface)

Son of sevenless homolog 1 (SOS1) is a universal guanine nucleotide exchange factor (GEF) that facilitates the transition of RAS proteins, including KRAS, from an inactive GDP-bound state to an active GTP-bound state [UniProt: Q07889]. This activation is a critical step in the MAPK/ERK signaling pathway, which regulates fundamental cellular processes such as growth, differentiation, and survival [PubMed: 30633532]. The SOS1–KRAS protein-protein interface has become a high-priority therapeutic target because many cancers are driven by KRAS mutations that keep the protein in a constitutively active state. Small molecule inhibitors targeting this interface bind to SOS1 and prevent its interaction with KRAS, thereby inhibiting the nucleotide exchange process and reducing RAS-GTP levels [PubMed: 33468548]. This "mutation-agnostic" strategy is particularly valuable as it can potentially inhibit a broad range of KRAS variants, including G12D, G12V, and G12C, and may synergize with direct KRAS inhibitors to overcome adaptive resistance [ClinicalTrials.gov: NCT04111458].

Other names

SOS1-KRAS interaction siteSOS1 catalytic pocketSOS1-RAS interface

Inhibition of the protein-protein interaction between the GEF SOS1 and KRAS, which prevents the exchange of GDP for GTP, thereby maintaining KRAS in its inactive state and suppressing downstream MAPK signaling [PubMed: 30633532].