Son of sevenless homolog 1 (SOS1) (SOS1)

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 P35240). The SOS1::KRAS interface is a critical node in the RAS/MAPK signaling pathway, which is frequently dysregulated in human malignancies through KRAS mutations (Hofmann et al., 2021, Cancer Discovery). BI 1701963 is a potent, small-molecule inhibitor that binds to the catalytic domain of SOS1, disrupting its interaction with KRAS and preventing the activation of both wild-type and various mutant forms of KRAS (Boehringer Ingelheim, 2023). By inhibiting this interaction, the drug effectively reduces downstream signaling through the RAF/MEK/ERK cascade, leading to decreased cell proliferation and survival in KRAS-driven tumors. This pan-KRAS approach is particularly valuable as it can potentially address a wide range of KRAS mutations and may be used in combination with direct KRAS inhibitors to prevent or overcome therapeutic resistance (ClinicalTrials.gov NCT04111458). Clinical studies have shown that SOS1 inhibition can sensitize KRAS-mutant cells to other targeted therapies, making it a versatile component of combination regimens (The Lancet Oncology, 2022).

Other names

SOS-1Guanine nucleotide exchange factor SOS1GF1GGF1GINGFNS4

Inhibition of the SOS1-KRAS protein-protein interaction to prevent the exchange of GDP for GTP, thereby maintaining KRAS in its inactive state and inhibiting downstream MAPK signaling.