SHY-855

SHY-855 is a pan RAS inhibitor. SHY-855 effectively prevents the binding of K-Ras proteins and other members of the Ras superfamily of small GTPases with IC₅₀ values of 0.3-5 μM. SHY-855 effectively inhibits the phosphorylation of MEK, ERK1/2, and AKT downstream of K-Ras. SHY-855 inhibits the formation of the Ras-GTP activity complex. SHY-855 can be used to the studies of pancreatic cancer and non-small cell lung cancer ^[1].

In Vitro, SHY-855 competes with GTP binding to K-Ras WT, the G12D, G12C, and Q61H mutants, as well as Rac-1, Rho-A, Rab5, and Rab35 with IC50s of 2.5, 2.5, 3, 5, 2.5, 2.5, 0.3 and 0.6 μM^[1]. SHY-855 (72 h) exhibits potent antiproliferative effects in multiple tumor cell lines, including pancreatic cancer (PANC-1, MIA PaCa-2, BxPC3) and non-small cell lung cancer (NCI-H1975, A549, NCI-H1299), with IC₅₀ values ranging from 0.75-2.9 μM^[1]. SHY-855 (0.3-10 μM, 6 h) significantly inhibits the phosphorylation of key signaling molecules induced by EGF in PANC-1, MIA PaCa-2 and NCI-H1975 cells^[1]. SHY-855 (1.25-10 μM, 6 h) inhibits Ras-GTP complex formation with an IC₅₀ of 1-3 μM in PANC-1, MIA PaCa-2 and NCI-H1975 cells^[1].

References:
[1]. Carta L, et al. Identification of Small-Molecule Inhibitors that Block the GTP-Binding Pocket of K-Ras and Other Members of the Ras Superfamily of Small GTPases. Mol Cancer Ther. 2025 Sep 12:OF1-OF10.