Synthesis of novel inhibitors blocking Wnt signaling downstream of β-catenin.
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.
Zoological Institute, Cell- and Developmental Biology, Karlsruhe Institute of Technology, D-76131 Karlsruhe, Germany.
Sonja
S
Halbedl
Marie-Claire
MC
Kratzer
Karolin
K
Rahm
Nicoletta
N
Crosta
Kye-Simeon
KS
Masters
Jessica
J
Zippert
Stefan
S
Bräse
Dietmar
D
Gradl
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D001757:Blastomeres / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D057809:HEK293 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000494:pharmacology; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C491761:AXIN2 protein, human; D000970:Antineoplastic Agents; D060466:Axin Protein; D051538:Hepatocyte Nuclear Factor 1-alpha; D010616:Phenanthrenes; D058118:Transcription Factor 7-Like 2 Protein; D029867:Xenopus Proteins; D051176:beta Catenin; C496490:hnf1a protein, Xenopus; C544896:tcf7l2 protein, Xenopus