Bromodomain and extraterminal domain protein bromodomain inhibitor based cancer therapeutics.

PURPOSE OF REVIEW: Bromodomain and extraterminal domain (BET) proteins are evolutionarily conserved, multifunctional super-regulators that specifically recognize acetyl-lysine on histones and other proteins controlling gene transcription. Several studies show that small molecules targeting these regulators preferentially suppress the transcription of cancer-promoting genes. Consequently, several BET inhibitors reached clinical trials and are in various stages for different kind of malignancies. In this review, we provide a concise summary of the molecular basis and preliminary clinical outcomes of BET inhibitors as anticancer therapeutics. RECENT FINDINGS: Results from early clinical trials with BET inhibitors confirmed their antitumor potential in both hematologic and solid tumours, but the evidence does not support the application of BET inhibitors as a monotherapy for cancer treatment. Treatment-emergent toxicities such as thrombocytopenia and gastrointestinal disorders are also reported. Preclinical data suggest that BET inhibitors may have a promising future in combination with other anticancer agents. SUMMARY: Despite of various challenges, BET inhibitors have high potential in combinatorial therapy and the future development of next-generation inhibitors could be promising. Further studies are needed to determine the predictive biomarkers for therapeutic response, which would translate into the long-term success of BET inhibitors as personalized medicines in cancer treatment.

The Small Molecule BC-2059 Inhibits Wingless/Integrated (Wnt)-Dependent Gene Transcription in Cancer through Disruption of the Transducin ß-Like 1-ß-Catenin Protein Complex.

The central role of ß-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 ß-catenin/transducin ß-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 ß-catenin. We identified two amino acids in a hydrophobic pocket of TBL1 that are required for binding with ß-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/ß-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 ß-like 1/ß-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.