Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612-9497, United States.
J Med Chem. 2021 Aug 26;64(16):12109-12131. doi: 10.1021/acs.jmedchem.1c00742. Epub 2021 Aug 12.
Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, , that binds with β-catenin and selectively disrupts the protein-protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI. dose-dependently suppresses β-catenin signaling activation, downregulates oncogenic β-catenin target genes, and abrogates invasiveness of β-catenin-dependent cancer cells. More importantly, shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model. This study offers a selective chemical probe to explore β-catenin-related biology and a drug-like small-molecule β-catenin/BCL9 disruptor for future drug development.
Wnt/β-catenin 信号通路的异常激活与许多疾病密切相关，包括癌症的侵袭和转移。靶向该通路核心信号节点β-catenin 的小分子药物是一种从生物学角度合理抑制β-catenin 信号过度激活的方法，但已证明这是一项艰巨的任务。在此，我们报告了一种类似药物的小分子 ，它与β-catenin 结合，并选择性地破坏 B 细胞淋巴瘤 9（BCL9）和β-catenin 之间的蛋白-蛋白相互作用（PPI），同时保留β-catenin/E-钙黏蛋白 PPI。 以剂量依赖性方式抑制β-catenin 信号激活，下调致癌β-catenin 靶基因，并阻断β-catenin 依赖性癌细胞的侵袭性。更重要的是， 在患者来源的异种移植小鼠模型中， 表现出良好的药代动力学特性，并能有效抑制β-catenin 靶基因的表达。这项研究提供了一种选择性的化学探针来探索β-catenin 相关生物学，以及一种类似药物的小分子β-catenin/BCL9 破坏剂，用于未来的药物开发。
