Selective Small Molecule Targeting β-Catenin Function Discovered by In Vivo Chemical Genetic Screen

Abstract

SUMMARY 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 novel compound, named windorphen, which 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 acetyl transferase, a co-activator that associates with β-catenin. Lastly, windorphen robustly and selectively kills cancer cells that harbor Wnt-activating mutations, supporting the therapeutic potential of this novel Wnt inhibitor class.

Direct Targeting of β-Catenin by a Small Molecule Stimulates Proteasomal Degradation and Suppresses Oncogenic Wnt/β-Catenin Signaling

“…Mutations in the pathway components, including APC, Axin, and β-catenin, have been found to be closely associated with various types of cancers (Korinek et al, 1997; Morin et al, 1997; Rubinfeld et al, 1997; Satoh et al, 2000). During the past decade, extensive efforts have focused on discovering small molecule inhibitors capable of downregulating such aberrant activation in cancer cells (Anastas and Moon, 2013; Fang et al, 2016; Hao et al, 2013; Kahn, 2014; Polakis, 2012). Compounds such as PKF115-584 and CGP049090 disrupt the interaction between β-catenin and TCF (Lepourcelet et al, 2004), ICG-001 interrupts binding between β-catenin and CBP (Emami et al, 2004) and carnosic acid interferes with β-catenin and BCL9 binding (de la Roche et al, 2012).…”

Triptonide Effectively Inhibits Wnt/β-Catenin Signaling via C-terminal Transactivation Domain of β-catenin

“…Pharmacological inhibition of GSK3 with GSK3 inhibitor BIO copies the “eyeless” phenotype152122. We examined whether triptonide can rescue the BIO-induced “eyeless” phenotype.…”

Identifying Novel Cancer Therapies Using Chemical Genetics and Zebrafish

“…More simply, small molecules can be used to inhibit oncogenic pathways already active during development. Hao et al used wild-type embryos to identify small molecule inhibitors of the Wnt pathway (Hao et al , 2013). Hits were determined by a straightforward morphological phenotype, specifically dorsoventral patterning (Hao et al , 2013).…”

“…Hao et al used wild-type embryos to identify small molecule inhibitors of the Wnt pathway (Hao et al , 2013). Hits were determined by a straightforward morphological phenotype, specifically dorsoventral patterning (Hao et al , 2013). The screen identified a small molecule, Windorphen, that selectively killed human cancer cells with aberrant Wnt signaling, including colon and prostate cancer cells (Hao et al , 2013).…”