Medicinal Chemistry Strategies for the Development of Inhibitors Disrupting β-Catenin’s Interactions with Its Nuclear Partners,Journal of Medicinal Chemistry

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Medicinal Chemistry Strategies for the Development of Inhibitors Disrupting β-Catenin’s Interactions with Its Nuclear Partners
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-12-30 , DOI: 10.1021/acs.jmedchem.2c01016
Hao Zhang _{1,

2} , Chenglong Liu ₁ , Di Zhu _{1,

3} , Qingwei Zhang ₂ , Jianqi Li ₂

Affiliation

Dysregulation of the Wnt/β-catenin signaling pathway is strongly associated with various aspects of cancer, including tumor initiation, proliferation, and metastasis as well as antitumor immunity, and presents a promising opportunity for cancer therapy. Wnt/β-catenin signaling activation increases nuclear dephosphorylated β-catenin levels, resulting in β-catenin binding to TCF and additional cotranscription factors, such as BCL9, CBP, and p300. Therefore, directly disrupting β-catenin’s interactions with these nuclear partners holds promise for the effective and selective suppression of the aberrant activation of Wnt/β-catenin signaling. Herein, we summarize recent advances in biochemical techniques and medicinal chemistry strategies used to identify potent peptide-based and small-molecule inhibitors that directly disrupt β-catenin’s interactions with its nuclear binding partners. We discuss the challenges involved in developing drug-like inhibitors that target the interactions of β-catenin and its nuclear binding partner into therapeutic agents.

中文翻译：

开发干扰 β-连环蛋白与其核伙伴相互作用的抑制剂的药物化学策略

Wnt/β-连环蛋白信号通路的失调与癌症的各个方面密切相关，包括肿瘤的发生、增殖和转移以及抗肿瘤免疫，并为癌症治疗提供了一个有希望的机会。Wnt/β-catenin 信号激活增加了核去磷酸化 β-catenin 水平，导致 β-catenin 与 TCF 和其他共转录因子（如 BCL9、CBP 和 p300）结合。因此，直接破坏 β-连环蛋白与这些核伙伴的相互作用有望有效和选择性地抑制 Wnt/β-连环蛋白信号传导的异常激活。在此处，我们总结了生化技术和药物化学策略的最新进展，这些策略用于鉴定直接破坏 β-连环蛋白与其核结合伙伴相互作用的强效肽基和小分子抑制剂。我们讨论了开发靶向 β-连环蛋白及其核结合伙伴相互作用的药物样抑制剂所面临的挑战。

更新日期：2022-12-30

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