2022
DOI: 10.1126/sciadv.abm3108
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A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer

Abstract: Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 compl… Show more

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Cited by 11 publications
(14 citation statements)
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References 86 publications
(127 reference statements)
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“…Additionally, the use of statins, which inhibits HMG-CoA reductase activity, has been associated with a reduced risk of developing CRC [ 126 ]. These studies may therefore provide therapeutic insights to the role of cholesterol in CRC tumorigenesis via the Wnt/YAP growth signalling pathway [ 65 ].…”
Section: The Role Of Lipids In Crcmentioning
confidence: 99%
“…Additionally, the use of statins, which inhibits HMG-CoA reductase activity, has been associated with a reduced risk of developing CRC [ 126 ]. These studies may therefore provide therapeutic insights to the role of cholesterol in CRC tumorigenesis via the Wnt/YAP growth signalling pathway [ 65 ].…”
Section: The Role Of Lipids In Crcmentioning
confidence: 99%
“…Due to the high binding of serum proteins, SAH-BCL9 peptides did not have pharmacokinetic properties conducive to clinical development. However, a novel β-catenin/BCL9 complex inhibitor E722-2648 is considered more effective than SAH-BCL9B [ 143 ]. In a previous study, E722-2648 could inhibit β-catenin/BCL9 complex formation and E722-2648 treatment could significantly reduce the tumor growth in the mice compared to the control group.…”
Section: Wnt Signaling Pathway In Crcmentioning
confidence: 99%
“…Yes-associated protein (YAP) expression is increased in CRC, and YAP oncogene expression is stimulated by Wnt/β-catenin signaling. Higher levels of YAP and β-catenin are found in the tumor cell nuclei ( Tanton et al, 2022 ). Ouahoud et al reported that the risk of developing CRC is reduced by statins, thus cholesterol plays an important role in CRC through Wnt/(YAP) growth signaling pathway ( Ouahoud et al, 2022 ; Tanton et al, 2022 ).…”
Section: Functions Of Fatty Acids In Cancer Cellsmentioning
confidence: 99%