title: I only have eye for ewe: the discovery of cyclopamine and development of Hedgehog pathway-targeting drugs.
abstract: Covering: 1950s to 2015During the 1950s, sheep ranchers in the western United States experienced episodic outbreaks of cyclopic lambs. In this highlight I describe how these mysterious incidents were traced to the grazing of Veratrum californicum wildflowers by pregnant ewes, leading to the discovery of cyclopamine () as a plant-derived teratogen. The precise mechanism of cyclopamine action remained enigmatic for 30 years, until this steroid alkaloid was found to be the first specific inhibitor of Hedgehog (Hh) signalling and a direct antagonist of the transmembrane receptor Smoothened (SMO). In addition to being a valuable probe of Hh pathway function, cyclopamine has been used to demonstrate the therapeutic potential of Hh pathway inhibitors. I discuss the development of SMO antagonists as anticancer therapies and emerging challenges.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. jameschen@stanford.edu and Department of Developmental Biology, Stanford University of School of Medicine, Stanford, CA 94305, USA.
authors.forename: James K
authors.initials: JK
authors.lastname: Chen
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D016142:Holoprosencephaly / Q000188:drug therapy; D006801:Humans; D015394:Molecular Structure; D011247:Pregnancy; D012756:Sheep; D015398:Signal Transduction; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors*; D014703:Veratrum / Q000737:chemistry; D014704:Veratrum Alkaloids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D053823:Hedgehog Proteins; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; C000541:cyclopamine