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Synthesis of novel inhibitors blocking Wnt signaling downstream of β‐Catenin
Author(s) -
Halbedl Sonja,
Kratzer Marie-Claire,
Rahm Karolin,
Crosta Nicoletta,
Masters Kye-Simeon,
Zippert Jessica,
Bräse Stefan,
Gradl Dietmar
Publication year - 2013
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2013.01.034
Subject(s) - blocking (statistics) , wnt signaling pathway , downstream (manufacturing) , catenin , microbiology and biotechnology , chemistry , signal transduction , biology , computer science , computer network , business , marketing
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.