Small-molecule inhibitors of the hedgehog signaling pathway as cancer therapeutics.
Inhibitors of the Hedgehog (Hh) molecular signaling pathway have emerged in recent years as a promising new class of potential therapeutics for cancer treatment. Numerous drug discovery efforts have resulted in the identification of a wide variety of small molecules that target different members of this pathway, including Smoothened (Smo), Sonic hedgehog protein (Shh), and Gli1. Several Smo inhibitors have now entered human clinical trials, and successful proof-of-concept studies have been carried out in patients with defined genetic mutations in the Hh pathway. This review provides a general overview of three main topics in this rapidly expanding area: 1) the various types of biological assays and in vivo models that have been employed for the identification and optimization of Hh pathway inhibitors; 2) Smo inhibitors reported to date, including recent clinical results where available; and 3) efforts toward the identification and characterization of inhibitors of other members of the Hh pathway.
Peukert
Stefan
S
Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA. stefan.peukert@novartis.com
Miller-Moslin
Karen
K
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D002460:Cell Line; D004195:Disease Models, Animal; D004345:Drug Industry; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000627:therapeutic use; D000072086:Smoothened Receptor
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D054852:Small Molecule Libraries; D000072086:Smoothened Receptor