Discovery of Small-Molecule Inhibitors of the PTK7/β-Catenin Interaction Targeting the Wnt Signaling Pathway in Colorectal Cancer,ACS Chemical Biology

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Discovery of Small-Molecule Inhibitors of the PTK7/β-Catenin Interaction Targeting the Wnt Signaling Pathway in Colorectal Cancer
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2022-04-28 , DOI: 10.1021/acschembio.1c00826
Laetitia Ganier _{1,

2} , Stephane Betzi _{2,

3} , Carine Derviaux ₃ , Philippe Roche _{2,

3} , Charlotte Dessaux ₁ , Christophe Muller ₃ , Laurent Hoffer ₂ , Xavier Morelli _{2,

3} , Jean-Paul Borg _{1,

4}

Affiliation

Colorectal cancer (CRC), the second cause of death due to cancer worldwide, is a major public health issue. The discovery of new therapeutic targets is thus essential. Pseudokinase PTK7 intervenes in the regulation of the Wnt/β-catenin pathway signaling, in part, through a kinase domain-dependent interaction with the β-catenin protein. PTK7 is overexpressed in CRC, an event associated with metastatic development and reduced survival of nonmetastatic patients. In addition, numerous alterations have been identified in CRC inducing constitutive activation of the Wnt/β-catenin pathway signaling through β-catenin accumulation. Thus, targeting the PTK7/β-catenin interaction could be of interest for future drug development. We have developed a NanoBRET screening assay recapitulating the interaction between PTK7 and β-catenin to identify compounds able to disrupt this protein–protein interaction. A high-throughput screening allowed us to identify small-molecule inhibitors targeting the Wnt pathway signaling and inducing antiproliferative and antitumor effects in vitro in CRC cells harboring β-catenin or adenomatous polyposis coli (APC) mutations. Thus, inhibition of the PTK7/β-catenin interaction could represent a new therapeutic strategy to inhibit cell growth dependent on the Wnt signaling pathway. Moreover, despite a lack of enzymatic activity of its tyrosine kinase domain, targeting the PTK7 kinase domain-dependent functions appears to be of interest for further therapeutic development.

中文翻译：

在结直肠癌中发现靶向 Wnt 信号通路的 PTK7/β-连环蛋白相互作用的小分子抑制剂

结直肠癌 (CRC) 是全球癌症死亡的第二大原因，是一个重大的公共卫生问题。因此，发现新的治疗靶点至关重要。假激酶 PTK7 干预 Wnt/β-catenin 通路信号传导的调节，部分是通过与 β-catenin 蛋白的激酶结构域依赖性相互作用。PTK7 在 CRC 中过度表达，这是一种与转移性发展和非转移性患者生存率降低相关的事件。此外，已在 CRC 中鉴定出许多改变，通过 β-连环蛋白积累诱导 Wnt/β-连环蛋白通路信号传导的组成性激活。因此，靶向 PTK7/β-catenin 相互作用可能对未来的药物开发很有意义。我们开发了一种 NanoBRET 筛选试验，概括了 PTK7 和 β-连环蛋白之间的相互作用，以鉴定能够破坏这种蛋白质-蛋白质相互作用的化合物。高通量筛选使我们能够识别针对 Wnt 通路信号传导并诱导抗增殖和抗肿瘤作用的小分子抑制剂在具有 β- 连环蛋白或腺瘤性结肠息肉病 (APC) 突变的 CRC 细胞中进行体外试验。因此，抑制 PTK7/β-catenin 相互作用可能代表一种新的治疗策略，以抑制依赖于 Wnt 信号通路的细胞生长。此外，尽管其酪氨酸激酶结构域缺乏酶活性，但靶向 PTK7 激酶结构域依赖性功能似乎对进一步的治疗开发很有意义。

更新日期：2022-04-28

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