Synthesis of novel inhibitors blocking Wnt signaling downstream of β-catenin

Sonja Halbedl; Marie-Claire Kratzer; Karolin Rahm; Nicoletta Crosta; Kye-Simeon Masters; Jessica Zippert; Stefan Bräse; Dietmar Gradl

doi:10.1016/j.febslet.2013.01.034

Synthesis of novel inhibitors blocking Wnt signaling downstream of β-catenin

FEBS Lett. 2013 Mar 1;587(5):522-7. doi: 10.1016/j.febslet.2013.01.034. Epub 2013 Jan 25.

Authors

Sonja Halbedl¹, Marie-Claire Kratzer, Karolin Rahm, Nicoletta Crosta, Kye-Simeon Masters, Jessica Zippert, Stefan Bräse, Dietmar Gradl

Affiliation

¹ Zoological Institute, Cell- and Developmental Biology, Karlsruhe Institute of Technology, D-76131 Karlsruhe, Germany.

PMID: 23357029
DOI: 10.1016/j.febslet.2013.01.034

Abstract

Large scale screening of libraries consisting of natural and small molecules led to the identification of many small molecule inhibitors repressing Wnt/β-Catenin signaling. However, targeted synthesis of novel Wnt pathway inhibitors has been rarely described. We developed a modular and expedient way to create the aromatic ring system with an aliphatic ring in between. Our synthesis opens up the possibility, in principle, to substitute all positions at the ring system with any desired substituent. Here, we tested five different haloquinone analogs carrying methoxy- and hydroxy-groups at different positions. Bona fide Wnt activity assays in cell culture and in Xenopus embryos revealed that two of these compounds act as potent inhibitors of aberrant activated Wnt/β-Catenin signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Axin Protein / genetics
Axin Protein / metabolism
Blastomeres / drug effects
Blastomeres / metabolism
Cell Line, Tumor
Gene Expression Regulation / drug effects
Genes, Reporter
HEK293 Cells
Hepatocyte Nuclear Factor 1-alpha / genetics
Hepatocyte Nuclear Factor 1-alpha / metabolism
Humans
Oocytes / drug effects
Oocytes / metabolism
Phenanthrenes / chemical synthesis*
Phenanthrenes / pharmacology
Transcription Factor 7-Like 2 Protein / genetics
Transcription Factor 7-Like 2 Protein / metabolism
Transcription, Genetic / drug effects
Wnt Signaling Pathway / drug effects*
Xenopus
Xenopus Proteins / genetics
Xenopus Proteins / metabolism
beta Catenin / genetics
beta Catenin / metabolism

Substances

AXIN2 protein, human
Antineoplastic Agents
Axin Protein
Hepatocyte Nuclear Factor 1-alpha
Phenanthrenes
Transcription Factor 7-Like 2 Protein
Xenopus Proteins
beta Catenin
hnf1a protein, Xenopus
tcf7l2 protein, Xenopus