title: Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action.
abstract: From a high content in vivo screen for modulators of developmental patterning in embryonic zebrafish, we previously identified eggmanone (EGM1, 3) as a Hedgehog (Hh) signaling inhibitor functioning downstream of Smoothened. Phenotypic optimization studies for in vitro probe development utilizing a Gli transcription-linked stable luciferase reporter cell line identified EGM1 analogs with improved potency and aqueous solubility. Mechanistic profiling of optimized analogs indicated two distinct scaffold clusters: PDE4 inhibitors able to inhibit downstream of Sufu, and PDE4-independent Hh inhibitors functioning between Smo and Sufu. Each class represents valuable in vitro probes for elucidating the complex mechanisms of Hh regulation.
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, PRB 383, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, 896 Preston Research Building, Nashville, TN 37232, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Hempel
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, PRB 383, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, 702 Light Hall, Nashville, TN 37232, USA.
authors.forename: Adrian G
authors.initials: AG
authors.lastname: Cadar
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, 2220 Pierce Avenue, PRB 383, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, 896 Preston Research Building, Nashville, TN 37232, USA; Research Medicine, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212, USA. Electronic address: charles.c.hong@vanderbilt.edu.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
mesh_terms: D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D058988:Phosphodiesterase 4 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D053823:Hedgehog Proteins; D058988:Phosphodiesterase 4 Inhibitors; D011744:Pyrimidinones; D012097:Repressor Proteins; C491023:SMO protein, human; C490764:SUFU protein, human; D000072086:Smoothened Receptor; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Eggmanone; Hedgehog signaling pathway; Phenotypic screening; Probe development; Suppressor of Fused