Son of sevenless homolog 1–KRAS interaction (SOS1–KRAS)

The SOS1–KRAS interaction is the catalytic interface between the guanine nucleotide exchange factor SOS1 and the small GTPase KRAS that promotes exchange of GDP for GTP, turning KRAS “on” and driving RAS–MAPK signaling central to cell proliferation and survival[3][4]. Small molecules such as BI-3406, BI-1701963, and MRTX0902 bind SOS1 at the KRAS-binding site and disrupt the SOS1–KRAS PPI, thereby decreasing KRAS-GTP levels and downstream ERK signaling, with antitumor activity in KRAS-driven models and enhanced efficacy in combinations (e.g., with KRAS G12C or EGFR inhibitors)[3][4][5][2]. Peptidic SAH-SOS1 mimetics derived from a SOS1 α-helix can also occupy the KRAS SOS1-binding pocket and reduce MAPK signaling, demonstrating the druggability of this PPI via interface engagement[1].

Other names

SOS1:KRAS interaction[3]SOS1–RAS interaction (KRAS-focused)[5]SOS1–KRAS protein–protein interaction (PPI)[3][4]SOS1 catalytic domain–KRAS interface[1]

Small-molecule inhibition of SOS1–KRAS binding, preventing SOS1-mediated guanine nucleotide exchange on KRAS and reducing KRAS-GTP levels[3][4][5]. Peptide disruption of the SOS1-binding pocket on KRAS (SAH-SOS1 peptides), directly occupying the SOS1–KRAS interface and attenuating downstream ERK–MAPK signaling[1]. Combination strategies: SOS1 inhibition enriches GDP-bound KRAS and blocks receptor tyrosine kinase–mediated activation of wild-type RAS, enhancing responses to KRAS G12C covalent inhibitors or EGFR inhibitors[5][2].