Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:41

Article

Shao, Hao¹  Li, Xiaokai^2,3  Hayashi, Shigenari³  Bertron, Jeanette L.^2,3  Schwarz, Daniel M. C.^2,3  Tang, Benjamin C.³  Gestwicki, Jason E.^2,3 

[1] Cent South Univ, Xiangya Hosp, Dept Oncol, Hunan Key Lab Mol Precis Med, Changsha 410008, Hunan, Peoples R China

[2] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94158 USA

关键词: Molecular chaperone;    Tauopathy;    Neurodegeneration;    Protein folding;    Metabolism;    Hsc70;    Hsp72;   

DOI  :  10.1016/j.bmcl.2021.128025

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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