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Ref Type Journal Article
PMID (18347139)
Authors Handeli S, Simon JA
Title A small-molecule inhibitor of Tcf/beta-catenin signaling down-regulates PPARgamma and PPARdelta activities.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 7 3 2008 Mar 521-9 Mol Cancer Ther
URL
Abstract Text Activation of the Wnt/beta-catenin signaling pathway occurs in several types of cancers and thus it is an attractive target for anticancer drug development. To identify compounds that inhibit this pathway, we screened a chemical library using a cell-based beta-catenin/Tcf-responsive reporter. We identified FH535, a compound that suppresses both Wnt/beta-catenin and peroxisome proliferator-activated receptor (PPAR) signaling. FH535 antagonizes both PPARgamma and PPARdelta ligand-dependent activation and shows structural similarity to GW9662, a known PPARgamma antagonist. The effect of FH535 on beta-catenin/Tcf activity is reduced in cells carrying a deletion of the PPARdelta gene, as well as by the PPARgamma agonist lysophosphatidic acid. Mechanistically, FH535 inhibits recruitment of the coactivators beta-catenin and GRIP1 but not the corepressors NCoR and SMRT. Its repression of beta-catenin recruitment, in comparison with GW9662, is linked to FH535's unique capability to inhibit the Wnt/beta-catenin signaling pathway. The antiproliferation effect of the compound observed on some transformed colon lung and liver cell lines is suggestive of its potential therapeutic value in the treatment of cancer.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
FH535 FH535 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
FH535 CTNNB1 Inhibitor 27 FH535 is PPAR antagonist and Wnt/CTNNB1 pathway inhibitor, which prevents cell proliferation (PMID: 18347139, PMID: 32681102).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC inact mut colon carcinoma sensitive FH535 Preclinical Actionable In a preclinical study, FH535 inhibited beta-catenin/TCF-dependent transactivation and demonstrated toxicity in colon carcinoma cells harboring an APC mutation in culture (PMID: 18347139). 18347139