TDI-003410

TDI-003410 is a small molecule inhibitor of Hedgehog acyltransferase (Hhat), an enzyme that catalyzes the palmitoylation of Sonic Hedgehog (Shh) ligands. This palmitoylation is essential for the biological activity and secretion of Hedgehog proteins. Developed by the Tri-Institutional Therapeutics Discovery Institute (TDI) in collaboration with Memorial Sloan Kettering Cancer Center, TDI-003410 targets the Hedgehog signaling pathway at its most upstream point, potentially overcoming resistance associated with downstream Smoothened (Smo) inhibitors. Preclinical studies in pancreatic ductal adenocarcinoma (PDAC) models have shown that TDI-003410 induces G2/M cell cycle arrest and apoptosis, significantly reducing tumor burden in both subcutaneous and orthotopic xenograft mouse models. Its ability to inhibit both canonical and non-canonical Hedgehog signaling makes it a unique therapeutic candidate for Shh-driven malignancies.