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 Gli1 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.