Son of sevenless homolog 1–Rat sarcoma virus protein-protein interface (SOS1–RAS interface)

The Son of sevenless homolog 1–Rat sarcoma virus (SOS1–RAS) protein-protein interface is a vital regulatory junction in the Ras/MAPK signaling pathway. SOS1 functions as a guanine nucleotide exchange factor (GEF) that promotes the activation of RAS GTPases by catalyzing the release of GDP and the binding of GTP (Hillig et al., 2019, PNAS). This molecular switch is fundamental for cellular processes such as proliferation, differentiation, and survival. In the context of oncology, many tumors are driven by KRAS mutations that lock RAS in an active state or increase its sensitivity to GEF-mediated activation; consequently, the SOS1–RAS interface has emerged as a high-priority therapeutic target (Hofmann et al., 2021, Cancer Discovery). Small molecule inhibitors designed to bind SOS1 disrupt its ability to interact with RAS, effectively reducing the levels of active RAS-GTP regardless of the specific KRAS mutation present. This approach is currently being evaluated in clinical trials, often in combination with direct KRAS inhibitors or MEK inhibitors, to overcome resistance mechanisms and enhance anti-tumor efficacy (Kessler et al., 2019, J. Med. Chem.).

Other names

SOS1-RAS interactionSOS1-KRAS interfaceSOS1-RAS complexSOS1:RAS PPI

Small molecule inhibition of the SOS1-RAS interaction to prevent the conversion of inactive GDP-bound RAS to active GTP-bound RAS.