Son of Sevenless homolog 1–RAS protein-protein interaction (SOS1–RAS PPI)

The Son of Sevenless homolog 1 (SOS1)–RAS protein-protein interaction is a fundamental component of the RAS/MAPK signaling cascade, where SOS1 serves as a guanine nucleotide exchange factor (GEF) for RAS GTPases including KRAS, HRAS, and NRAS (UniProt Q07889). By facilitating the exchange of GDP for GTP, SOS1 converts RAS into its active conformation, triggering downstream pathways that regulate cell growth, proliferation, and survival (Hillig et al., 2019, PNAS). Dysregulation of this interaction is a hallmark of various cancers, especially those driven by KRAS mutations, which account for approximately 25% of all human tumors (Hofmann et al., 2021, Cancer Discovery). Additionally, germline mutations in SOS1 are associated with Noonan syndrome, a developmental disorder (Roberts et al., 2007, Nature Genetics). Pharmacological targeting of the SOS1–RAS interface aims to lock RAS in its inactive state, providing a "pan-RAS" therapeutic approach that can inhibit multiple RAS isoforms and mutants (Kessler et al., 2019, PNAS). Current clinical candidates like BI-1701963 and MRTX0902 are being investigated as monotherapies or in combination with KRAS G12C inhibitors to prevent adaptive resistance and enhance anti-tumor efficacy (ClinicalTrials.gov NCT04111458). This target is particularly valuable because it addresses the historically "undruggable" nature of many RAS mutants by targeting their common activator.

Other names

SOS1-KRAS interactionSOS1-RAS complexSOS1-HRAS interactionSOS1-NRAS interactionSOS1-mediated RAS activation

Small molecule inhibitors bind to the SOS1 protein, typically at the catalytic site or an allosteric pocket, to disrupt its physical interaction with RAS GTPases. This prevents SOS1 from catalyzing the exchange of GDP for GTP, thereby maintaining RAS in its inactive state and inhibiting downstream oncogenic signaling through the MAPK/ERK pathway.