Inhibition of the hedgehog (Hh) pathway represents an exciting new intervention strategy toward the development of cancer chemotherapeutics due to its integral role in the development of a variety of human cancers.
1. Recent studies have demonstrated that several forms of the vitamin D class of seco-steroids inhibit Hh signaling. The development of vitamin D3 analogues rationally designed to exert their anti-cancer effects through the Hh pathway would represent an improved class of vitamin D-based anti-cancer chemotherapeutics. Several classes of vitamin D3 analogues are currently under development in the Hadden lab as selective Hh pathway inhibitors.
2.The clinically efficacious anti-fungal itraconazole has been recently identified as an inhibitor of both Hh signaling and angiogenesis. The Hadden lab is actively involved in repurposing the itraconazole scaffold to exploit these promising anti-cancer properties.
Oxysterols (OHCs) are byproducts of cholesterol oxidation that exert numerous physiological effects through a variety of cellular receptors. Several natural and synthetic OHCs have demonstrated the ability to activate Hh signaling in vitro and in vivo, suggesting their potential as chemical probes for understanding endogenous mechanisms of Hh modulation and therapeutic agents for Hh-associated neurodegenerative disorders and orthopedic indications The Hadden lab is currently synthesizing and evaluating several series of oxysterol analogues as Hh pathway agonists for the potential use as novel neuroprotective agents.