title: Hedgehog pathway inhibitors: a patent review (2009--present).
abstract: BACKGROUND
  The hedgehog (Hh) pathway is a developmental signaling pathway that plays a key role in directing cellular growth and tissue patterning during embryonic development. Dysregulation of Hh signaling has been linked to the development of a variety of human tumors, and numerous drug development programs in both academia and industry are actively exploring inhibitors of the pathway as anti-cancer agents.
  
  
  METHODS
  This review surveys the recent patent literature (2009 - 2012) for Hh pathway inhibitors as treatments for a variety of human malignancies.
  
  
  CONCLUSIONS
  To date, all of the pathway inhibitors that have entered clinical trials and the majority of compounds identified via high-throughput screens target smoothened (Smo), a transmembrane protein that is essential for pathway signaling. While these compounds have shown initial promise in preclinical and clinical trials, several mechanisms of resistance to Smo inhibitors have been identified. Even with this knowledge, the majority of small-molecule pathway inhibitors disclosed in the recent patent literature directly target Smo. The continued identification of Hh pathway inhibitors that function either upstream or downstream is warranted not only to combat these emerging resistance mechanisms, but also to help elucidate the various cellular mechanisms that control both normal and oncogenic pathway signaling.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA kyle.hadden@uconn.edu
authors.forename: Matthew Kyle
authors.initials: MK
authors.lastname: Hadden
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy; D010330:Patents as Topic; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor