Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.).
Applied Cancer Research and Drug Discovery, Translational Genomics Research Institute (TGen), Phoenix, Arizona (R.S., T.G.H., S.S., A.W., T.T., R.R.d.V., K.D., M.R.K., S.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.V.); MD Anderson Cancer Center, University of Texas, Department of Leukemia, Division of Cancer Medicine, Houston, Texas (K.N.B.); Iterion Therapeutics, Inc., Houston, Texas (S.K.H.); College of Medicine, Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (S.K.B.); City of Hope Comprehensive Cancer Center, Duarte, California (R.S.)
J Pharmacol Exp Ther. 2021 Aug;378(2):77-86. doi: 10.1124/jpet.121.000634. Epub 2021 May 18.
The central role of -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 -catenin/transducin -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 -catenin. We identified two amino acids in a hydrophobic pocket of TBL1 that are required for binding with -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 NFB subunit, BC-2059 failed to disrupt the interaction of TBL1 with either NCoR/SMRT or NFB. Together, our results show that BC-2059 selectively targets TBL1/-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 -like 1/-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.
-连环蛋白在 Wnt 通路中的核心作用使其成为异常 Wnt 信号驱动的癌症的有吸引力的治疗靶点。我们最近开发了一种小分子抑制剂 BC-2059，它通过一种未知的作用机制破坏β-连环蛋白/转导素样 1（TBL1）复合物，从而促进细胞凋亡。在这项研究中，我们表明 BC-2059 与 TBL1 高亲和力直接相互作用，当与β-连环蛋白复合物时。我们确定了 TBL1 中一个疏水口袋中的两个氨基酸，这些氨基酸是与β-连环蛋白结合所必需的，计算建模预测 BC-2059 与该疏水口袋相互作用。尽管 TBL1 中的这个口袋参与与 NCoR/SMRT 复合物成员 G 蛋白通路抑制剂 2（GSP2）和 SMRT 和 p65 NFB 亚基的结合，但 BC-2059 未能破坏 TBL1 与 NCoR/SMRT 或 NFB 的相互作用。总之，我们的结果表明 BC-2059 选择性靶向 TBL1/-连环蛋白蛋白复合物，表明 BC-2059 是一种治疗异常 Wnt 信号通路肿瘤的药物。意义声明：本研究报告了一种新型 Wnt 通路抑制剂的作用机制，该抑制剂的特征是选择性破坏转导素样 1/-连环蛋白蛋白复合物。由于 Wnt 信号在癌症类型中失调，因此本研究表明 BC-2059 有可能使依赖该途径的肿瘤患者受益。
