title: A small molecule that binds Hedgehog and blocks its signaling in human cells.
abstract: Small-molecule inhibition of extracellular proteins that activate membrane receptors has proven to be extremely challenging. Diversity-oriented synthesis and small-molecule microarrays enabled the discovery of robotnikinin, a small molecule that binds the extracellular Sonic hedgehog (Shh) protein and blocks Shh signaling in cell lines, human primary keratinocytes and a synthetic model of human skin. Shh pathway activity is rescued by small-molecule agonists of Smoothened, which functions immediately downstream of the Shh receptor Patched.
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Benjamin Z
authors.initials: BZ
authors.lastname: Stanton
authors.forename: Lee F
authors.initials: LF
authors.lastname: Peng
authors.forename: Nicole
authors.initials: N
authors.lastname: Maloof
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakai
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Jay L
authors.initials: JL
authors.lastname: Duffner
authors.forename: Kennedy M
authors.initials: KM
authors.lastname: Taveras
authors.forename: Joel M
authors.initials: JM
authors.lastname: Hyman
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
authors.forename: Angela N
authors.initials: AN
authors.lastname: Koehler
authors.forename: James K
authors.initials: JK
authors.lastname: Chen
authors.forename: Julia L
authors.initials: JL
authors.lastname: Fox
authors.forename: Anna
authors.initials: A
authors.lastname: Mandinova
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D016475:3T3 Cells; D000818:Animals; D055808:Drug Discovery; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007769:Lactams / Q000378:metabolism / Q000494:pharmacology*; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D000072079:Patched Receptors; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D053823:Hedgehog Proteins; D007769:Lactams; D007783:Lactones; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C539164:robotnikinin