RT Journal Article
SR Electronic
T1 The Small Molecule BC-2059 Inhibits Wingless/Integrated (Wnt)-Dependent Gene Transcription in Cancer through Disruption of the Transducin <em>β</em>-Like 1-<em>β</em>-Catenin Protein Complex
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 77
OP 86
DO 10.1124/jpet.121.000634
VO 378
IS 2
A1 Raffaella Soldi
A1 Tithi Ghosh Halder
A1 Samuel Sampson
A1 Hariprasad Vankayalapati
A1 Alexis Weston
A1 Trason Thode
A1 Kapil N. Bhalla
A1 Serina Ng
A1 Ryan Rodriguez del Villar
A1 Kevin Drenner
A1 Mohan R. Kaadige
A1 Stephen K. Horrigan
A1 Surinder K. Batra
A1 Ravi Salgia
A1 Sunil Sharma
YR 2021
UL http://jpet.aspetjournals.org/content/378/2/77.abstract
AB 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 G Protein Pathway Suppressor 2 (GSP2) and SMRT and p65 NFκB subunit, BC-2059 failed to disrupt the interaction of TBL1 with either NCoR/SMRT or NFκB. 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 transducin β-like 1/β-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.