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 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.