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多酚衍生物作为 DYRK1A 抑制剂的设计、合成与生物学评价。多发性硬化症潜在有希望的治疗方法的发现。

Design, synthesis, and biological evaluation of polyphenol derivatives as DYRK1A inhibitors. The discovery of a potentially promising treatment for Multiple Sclerosis.

机构信息

Avanti Biosciences, Inc. 3210 Merryfield Row, San Diego, CA 92121, United States.

Department of Molecular Biology, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, United States.

出版信息

Bioorg Med Chem Lett. 2022 May 15;64:128675. doi: 10.1016/j.bmcl.2022.128675. Epub 2022 Mar 12.

DOI:10.1016/j.bmcl.2022.128675
PMID:35292341
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9067539/
Abstract

Green tea and its natural components are known for their usefulness against a variety of diseases. In particular, the activity of main catechin Epigallocatechin gallate (EGCG) against Dual-specificity tyrosine-(Y)-phosphorylation Regulated Kinase-1A (DYRK1A) has been reported; here we are showing a structure-activity relationship (SAR) for EGCG against this molecular target. We have studied the influence of all four rings on the activity and the nature of its absolute geometry. This work has led to the identification of the more potent and stable trans fluoro-catechin derivative 1f (IC = 35 nM). This molecule together with a novel delivery method showed good efficacy in vivo when tested in a validated model of multiple sclerosis (EAE).

摘要

绿茶及其天然成分以其对多种疾病的有益作用而闻名。特别是，主要儿茶素表没食子儿茶素没食子酸酯（EGCG）对双特异性酪氨酸-（Y）-磷酸化调节激酶-1A（DYRK1A）的活性已被报道；在这里，我们展示了 EGCG 针对这一分子靶标的构效关系（SAR）。我们研究了四个环对活性的影响及其绝对几何形状的性质。这项工作导致了更有效和稳定的反式氟儿茶素衍生物 1f（IC = 35 nM）的鉴定。当在多发性硬化症（EAE）的验证模型中进行测试时，该分子及其新型给药方法表现出良好的体内疗效。

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本文引用的文献

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Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation.治疗药物增强小胶质细胞 p21-Nrf2 轴可以挽救神经炎症引起的神经退行性变。
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Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer's disease.新型强效选择性口服 DYRK1A 抑制剂 SM07883 降低 Tau 病理学：阿尔茨海默病的潜在治疗方法。
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LPS-Induced Inflammation Abolishes the Effect of DYRK1A on IkB Stability in the Brain of Mice.脂多糖诱导的炎症会破坏 DYRK1A 对小鼠大脑中 IkB 稳定性的影响。
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