SOS1-IN-2

BI-3406 is an inhibitor of the protein-protein interaction between K-Ras and the guanine nucleotide exchange factor son of sevenless homolog 1 (SOS1; IC₅₀ = 5 nM).¹ It selectively disrupts the protein-protein interaction between K-Ras^G12C or K-Ras^G12D with SOS1 over SOS2, and it is selective over 321 kinases in a panel at 10 ?M but does inhibit PLK4, BMPR2, and LRRK2 activity by greater than 50%. BI-3406 inhibits the growth of DLD-1, A549, NCI H23, and NCI H358 cells expressing mutant K-Ras (IC₅₀s = 16-52 nM) but not NCI H520 and A375 cells expressing wild-type K-Ras. BI-3406 (12 or 50 mg/kg, twice per day) reduces tumor growth in an MIA PaCa-2 mouse xenograft model.

1.Hofmann, M.H., Gmachl, M., Ramharter, J., et al.BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibitionCancer Discov.11(1)142-157(2021)