Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States; The Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, United States.
Bioorg Chem. 2022 Jul;124:105812. doi: 10.1016/j.bioorg.2022.105812. Epub 2022 Apr 15.
The Wnt/β-catenin signaling pathway plays extensive roles in cancer initiation, proliferation, and development, and has been implicated in the regulation of stem cells in the intestinal crypt, widely accepted as responsible for colorectal cancer (CRC) origination. This pathway has been a target of interest for many years for chemotherapeutic development of CRC due to its implication in most cases. Previously, a series of naphthoquinone analogs have been identified to inhibit the Wnt/β-catenin. It was postulated that these compounds exhibit their inhibitory activity via binding to β-catenin at the β-catenin/TCF4 interaction interface. In this study, we aimed to further define the critical pharmacophore for these compounds and verify their mechanisms of action for their abilities to inhibit the Wnt/β-catenin signaling pathway. Interestingly, our data suggested two of the compounds, compounds 3 and 6, may potently inhibit the Wnt/β-catenin signaling pathway via inhibition of the TCF4/DNA interaction, a novel finding compared to previous studies on these compounds. Our computational studies suggested that the compounds bound within the DNA binding HMG-box domain of TCF4 to elicit their inhibitory action. These compounds inhibited Wnt signaling in a dose dependent manner, suppressed Wnt direct target genes and demonstrated unforeseen degradation of the TCF4 protein. Thus, this study revealed a potentially novel mechanism of action of the chloro-naphthoquinone as possibly a multi-targeting scaffold, which warrants further investigation in future drug discovery on the 'undruggable" TCF proteins and an aberrantly activated Wnt/β-catenin signaling pathway.
Wnt/β-连环蛋白信号通路在癌症的发生、增殖和发展中发挥着广泛的作用，并被认为参与了肠道隐窝干细胞的调节，这被广泛认为是结直肠癌（CRC）起源的原因。由于该通路在大多数情况下都有涉及，多年来一直是开发 CRC 化疗药物的目标。以前，已经确定了一系列萘醌类似物来抑制 Wnt/β-连环蛋白。据推测，这些化合物通过与β-连环蛋白在β-连环蛋白/TCF4 相互作用界面结合来发挥其抑制活性。在这项研究中，我们旨在进一步确定这些化合物的关键药效团，并验证它们抑制 Wnt/β-连环蛋白信号通路的作用机制。有趣的是，我们的数据表明，两种化合物，化合物 3 和 6，可能通过抑制 TCF4/DNA 相互作用来有效抑制 Wnt/β-连环蛋白信号通路，这与之前对这些化合物的研究相比是一个新的发现。我们的计算研究表明，这些化合物结合在 TCF4 的 DNA 结合 HMG 盒结构域内，以发挥其抑制作用。这些化合物以剂量依赖的方式抑制 Wnt 信号，抑制 Wnt 直接靶基因，并显示出 TCF4 蛋白的意外降解。因此，这项研究揭示了氯萘醌可能作为多靶标支架的潜在作用机制，这值得在未来的“不可成药”TCF 蛋白和异常激活的 Wnt/β-连环蛋白信号通路的药物发现中进一步研究。
