用于减少 Tau 蛋白聚集的 Aha1/Hsp90 复合物小分子干扰剂的合成与评估
Synthesis and Evaluation of Small Molecule Disruptors of the Aha1/Hsp90 Complex for the Reduction of Tau Aggregation.
作者信息
Keegan Bradley M, Catalfano Kevin C, Banerjee Monimoy, Blagg Brian S J
机构信息
Warren Center for Drug Discovery, Department of Chemistry and Biochemistry, University of Notre Dame, 310 McCourtney Hall, Notre Dame, Indiana 46556, United States.
出版信息
ACS Med Chem Lett. 2022 Apr 15;13(5):827-832. doi: 10.1021/acsmedchemlett.2c00064. eCollection 2022 May 12.
KU-177 was recently shown to disrupt interactions between Hsp90 and Aha1 . Subsequent studies in recombinant thioflavin T (ThT) assays demonstrated that KU-177 ablates Aha1-driven enhancement of Hsp90-dependent tau aggregation, which was confirmed by TEM. Using KU-177 as a lead compound, derivatives of KU-177 were synthesized and evaluated for their ability to disrupt Aha1/Hsp90 interactions and inhibit P301L tau aggregation. Preliminary structure-activity relationships were revealed, which led to the identification of a new lead compound that contains a -like amide bond. The new lead compounds retain the ability to disrupt Aha1/Hsp90 interactions in SH-SY5Y and SK-BR-3 cells without direct inhibition of Hsp90, providing a new scaffold for subsequent drug discovery efforts.
KU-177最近被证明能破坏热休克蛋白90（Hsp90）与Aha1之间的相互作用。随后在重组硫黄素T（ThT）分析中的研究表明，KU-177消除了Aha1驱动的Hsp90依赖性tau蛋白聚集增强，这一点通过透射电子显微镜（TEM）得到了证实。以KU-177作为先导化合物，合成了KU-177的衍生物，并评估了它们破坏Aha1/Hsp90相互作用和抑制P301L tau蛋白聚集的能力。揭示了初步的构效关系，从而确定了一种含有类似酰胺键的新先导化合物。新的先导化合物保留了在SH-SY5Y和SK-BR-3细胞中破坏Aha1/Hsp90相互作用的能力，而不会直接抑制Hsp90，为后续的药物研发工作提供了一个新的框架。
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