RU-SKI 101

RU-SKI 101 is a small molecule inhibitor of Hedgehog Acyltransferase (Hhat), an enzyme belonging to the membrane-bound O-acyltransferase (MBOAT) family. Hhat is responsible for the palmitoylation of Sonic Hedgehog (Shh), a critical post-translational modification required for Shh to function as a signaling morphogen. By blocking Hhat activity, RU-SKI 101 inhibits both autocrine and paracrine Hedgehog signaling pathways, which are frequently overexpressed and drive tumor progression in various cancers, most notably pancreatic adenocarcinoma. Developed at Memorial Sloan-Kettering Cancer Center as a second-generation analog of RU-SKI 43, RU-SKI 101 demonstrates significantly improved potency with an in vitro IC50 of 156 nM and has been evaluated in preclinical models for its potential as an anti-cancer therapeutic.