Discovery of First-in-Class TAK1-MKK3 Protein-Protein Interaction (PPI) Inhibitor (R)-STU104 for the Treatment of Ulcerative Colitis through Modulating TNF-α Production.
Discovery of First-in-Class TAK1-MKK3 Protein-Protein Interaction (PPI) Inhibitor (R)-STU104 for the Treatment of Ulcerative Colitis through Modulating TNF-α Production.
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DOI：
10.1021/acs.jmedchem.1c02198
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发表时间：
2022-04
影响因子：
7.3
通讯作者：
M. Tang;Haidong Li;J. Ning;Xiaoyan Shen;Xun Sun
中科院分区：
文献类型：
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作者：
M. Tang;Haidong Li;J. Ning;Xiaoyan Shen;Xun Sun
肿瘤坏死因子α（TNF-α）已被证明是自身免疫性疾病的治疗靶点。然而，这种生物疗法存在一些不可避免的缺点，例如感染风险。因此，仍然需要针对 TNF-α 产生信号通路的小分子替代品。在此，我们描述了 3-aryindanone 化合物在调节 TNF-α 产生方面的设计、合成和构效关系。其中，(R)-STU104对TNF-α的产生表现出最有效的抑制活性，它通过与MKK3结合并破坏TAK1磷酸化MKK3来抑制TAK1/MKK3/p38/MnK1/MK2/elF4E信号通路。结果，(R)-STU104 在急性和慢性小鼠 UC 模型中表现出显着的剂量效应关系。除了良好的药代动力学 (PK) 和安全性外，(R)-STU104 在 10 mg/kg/d 剂量下表现出比 50 mg/kg/d 剂量的美沙拉嗪更好的体内抗 UC 功效。这些结果表明 TAK1-MKK3 相互作用抑制剂有可能用于治疗 UC。
Tumor necrosis factor α (TNF-α) has been demonstrated to be a therapeutic target for autoimmune diseases. However, this biological therapy exhibits some inevitable disadvantages, such as risk of infection. Thus, small-molecule alternatives by targeting TNF-α production signaling pathway are still in demand. Herein, we describe the design, synthesis, and structure-activity relationships of 3-aryindanone compounds regarding their modulation of TNF-α production. Among them, (R)-STU104 exhibited the most potent inhibitory activity on TNF-α production, which suppressed the TAK1/MKK3/p38/MnK1/MK2/elF4E signal pathways through binding with MKK3 and disrupting the TAK1 phosphorylating MKK3. As a result, (R)-STU104 demonstrated remarkable dose-effect relationships on both acute and chronic mouse UC models. In addition to its good pharmacokinetic (PK) and safety profile, (R)-STU104 showed better anti-UC efficacy in vivo at 10 mg/kg/d than mesalazine at the dose of 50 mg/kg/d. These results suggested that TAK1-MKK3 interaction inhibitors could be potentially utilized for the treatment of UC.