Discovery of Hedgehog Antagonists for Cancer Therapy

Background: The evolutionarily conserved Hedgehog (Hh) signaling cascade is one of the key mediators of embryonic development of many metazoans. This pathway has been extensively targeted by small molecule inhibitors as its misregulation leads to various malignancies and developmental disorders. Thus, blocking this pathway can be a novel therapeutic avenue for the treatment of Hedgehog-dependent cancers. This review covers the mechanism of hedgehog signaling in vertebrate cells, provides an overview of reported small molecule Hh pathway inhibitors, with the synthetic routes and SAR studies of some of them discussed briefly. Methods: A comprehensive survey of literature related to synthetic and naturally occurring Hh signaling antagonists reported till date is presented. Results: Given the selectivity of small molecules targeting, this pathway for cancer treatment compared to kinase, tubulin or HDAC inhibitors, several such antagonists have been discovered, of which some are in preclinical development and clinical studies. Most of the reported small molecules primarily antagonize the Smoothened receptor although agents targeting Glil transcription factor and Shh ligand have also been discovered. Till date, nine Smo antagonists have been evaluated in clinical trials. GDC-0449/Vismodegib and NVP-LDE225/Erismodegib, were granted approval by the U.S. Food and Drug Administration (U.S. FDA) for the treatment of basal cell carcinoma. Conclusion: The challenge is to identify agents that target the pathway downstream of Smo and develop strategies to overcome acquired drug resistance to the current Smo inhibitors with deeper understanding of the resistance mechanisms.