title: Selective small molecule targeting β-catenin function discovered by in vivo chemical genetic screen.
abstract: The canonical Wnt signaling pathway, mediated by the transcription factor β-catenin, plays critical roles in embryonic development and represents an important therapeutic target. In a zebrafish-based in vivo screen for small molecules that specifically perturb embryonic dorsoventral patterning, we discovered a compound named windorphen that selectively blocks the Wnt signal required for ventral development. Windorphen exhibits remarkable specificity toward β-catenin-1 function, indicating that the two β-catenin isoforms found in zebrafish are not functionally redundant. We show that windorphen is a selective inhibitor of p300 histone acetyltransferase, a coactivator that associates with β-catenin. Finally, windorphen robustly and selectively kills cancer cells that harbor Wnt-activating mutations, supporting the therapeutic potential of this Wnt inhibitor class.
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Jijun
authors.initials: J
authors.lastname: Hao
authors.forename: Ada
authors.initials: A
authors.lastname: Ao
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Clare K
authors.initials: CK
authors.lastname: Murphy
authors.forename: Audrey Y
authors.initials: AY
authors.lastname: Frist
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Keel
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Thorne
authors.forename: Kwangho
authors.initials: K
authors.lastname: Kim
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009154:Mutation; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects; D015027:Zebrafish; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051153:Wnt Proteins; D051176:beta Catenin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor