Condensate screening identifies YM155 as β-catenin condensate inhibitor in colorectal cancer

β-catenin is a transcriptional cofactor crucial in forming biomolecular condensates that drive WNT target gene transcription. Its pathological accumulation in the nucleus is a critical step in WNT-driven cancers, such as colorectal cancer. Disrupting β-catenin condensates is a promising cancer treat...

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Published in:bioRxiv
Main Authors: Manzato, Caterina, Sirati, Nafiseh, Knol, Bronwen A, Kuiken, Hendrik J, Morris, Ben, Fleming, Cassio, Beijersbergen, Roderick L, Schuijers, Jurian
Format: Paper
Language:English
Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.01.2025
Cold Spring Harbor Laboratory
Edition:1.1
Subjects:
Antineoplastic drugs
Cancer therapies
Colorectal carcinoma
Condensates
Molecular Biology
Nanobodies
Organoids
Transcription
Wnt protein
β-Catenin
ISSN:2692-8205, 2692-8205
Online Access:Get full text
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Summary:β-catenin is a transcriptional cofactor crucial in forming biomolecular condensates that drive WNT target gene transcription. Its pathological accumulation in the nucleus is a critical step in WNT-driven cancers, such as colorectal cancer. Disrupting β-catenin condensates is a promising cancer treatment strategy, but no clinical applications currently exist. In this study, we developed a Nanobody Enabled Condensate Observation (NECO) screening platform to identify small molecules that modulate β-catenin condensates. The platform revealed compounds that either enhanced or reduced β-catenin transcriptional condensates. Among them, YM155 (sepantronium bromide) was identified as an inhibitor, disrupting essential weak interactions for condensate formation. This disruption effectively inhibits the proliferation of WNT-driven colorectal cancer organoids. These findings show that the NECO platform can identify small molecules that target β-catenin condensates and suggest YM155 as a potential anti-cancer agent for colorectal cancer.Competing Interest StatementThe authors have declared no competing interest.
Bibliography:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
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Competing Interest Statement: The authors have declared no competing interest.
ISSN:2692-8205
2692-8205
DOI:10.1101/2025.01.13.632724