title: Discovery of Hedgehog Antagonists for Cancer Therapy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032. India.
authors.forename: Harleen
authors.initials: H
authors.lastname: Khatra
authors.affiliation: Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032. India.
authors.forename: Chandra
authors.initials: C
authors.lastname: Bose
authors.affiliation: Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032. India.
authors.forename: Surajit
authors.initials: S
authors.lastname: Sinha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D054852:Small Molecule Libraries
keywords: GLI; Hedgehog pathway; anticancer; inhibitors; small molecule; smoothened