热休克蛋白 70（Hsp70）抑制剂增强代谢稳定性可降低 tau 水平。
Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels.
机构信息
Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, United States; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, United States.
出版信息
Bioorg Med Chem Lett. 2021 Jun 1;41:128025. doi: 10.1016/j.bmcl.2021.128025. Epub 2021 Apr 9.
The molecular chaperone, Heat Shock Protein 70 (Hsp70), is an emerging drug target for neurodegenerative diseases, because of its ability to promote degradation of microtubule-associated protein tau (MAPT/tau). Recently, we reported YM-08 as a brain penetrant, allosteric Hsp70 inhibitor, which reduces tau levels. However, the benzothiazole moiety of YM-08 is vulnerable to metabolism by CYP3A4, limiting its further application as a chemical probe. In this manuscript, we designed and synthesized seventeen YM-08 derivatives by systematically introducing halogen atoms to the benzothiazole ring and shifting the position of the heteroatom in a distal pyridine. In microsome assays, we found that compound JG-23 has 12-fold better metabolic stability and it retained the ability to reduce tau levels in two cell-based models. These chemical probes of Hsp70 are expected to be useful tools for studying tau homeostasis.
热休克蛋白 70（Hsp70）是一种分子伴侣，它能够促进微管相关蛋白 tau（MAPT/tau）的降解，因此成为神经退行性疾病的一个新兴药物靶点。最近，我们报道了 YM-08 是一种脑穿透性、别构 Hsp70 抑制剂，可降低 tau 水平。然而，YM-08 的苯并噻唑部分容易被 CYP3A4 代谢，限制了它作为化学探针的进一步应用。在本手稿中，我们通过系统地在苯并噻唑环上引入卤素原子并改变远端吡啶中杂原子的位置，设计并合成了十七个 YM-08 衍生物。在微粒体测定中，我们发现化合物 JG-23 的代谢稳定性提高了 12 倍，并且在两种基于细胞的模型中仍具有降低 tau 水平的能力。这些 Hsp70 的化学探针有望成为研究 tau 动态平衡的有用工具。
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