The small molecule BC-2059 inhibits Wnt-dependent gene transcription in cancer through disruption of the Transducin Beta-Like 1 (TBL1)-β-catenin protein complex.

The central role of β-catenin in the Wnt pathway makes it an attractive therapeutic target for cancers driven by aberrant Wnt signaling. We recently developed a small molecule inhibitor, BC-2059, that promotes apoptosis by disrupting the β-catenin /transducin β-like 1 (TBL1) complex through an unknown mechanism of action. In this study, we show that BC-2059 directly interacts with high affinity for TBL1 when in complex with β-catenin. We identified two amino acids in a hydrophobic pocket of TBL1 that are required for binding with β-catenin, and computational modeling predicted that BC-2059 interacts at the same hydrophobic pocket. Although this pocket in TBL1 is involved in binding with NCoR/SMRT complex members GSP2 and SMRT and p65 NFkB subunit, BC-2059 failed to disrupt the interaction of TBL1 with either NCoR/SMRT or NFkB. Together, our results show that BC-2059 selectively targets TBL1/β-catenin protein complex, suggesting BC-2059 as a therapeutic for tumors with deregulated Wnt signaling pathway. Significance Statement This study reports the mechanism of action of a novel Wnt pathway inhibitor, characterizing the selective disruption of the TBL1/b-catenin protein complex. As Wnt signaling is dysregulated across cancer types, this study suggests BC-2059 has the potential to benefit patients with tumors reliant on this pathway.