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

• Published in: Bioorganic & medicinal chemistry letters Vol. 41; p. 128025
• Main Authors: Shao, Hao, Li, Xiaokai, Hayashi, Shigenari, Bertron, Jeanette L., Schwarz, Daniel M.C., Tang, Benjamin C., Gestwicki, Jason E.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.06.2021; Elsevier
• Subjects: Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Hsc70; HSP70 Heat-Shock Proteins - antagonists & inhibitors; HSP70 Heat-Shock Proteins - metabolism; Hsp72; Humans; Life Sciences & Biomedicine; Metabolism; Molecular chaperone; Molecular Structure; Neurodegeneration; Pharmacology & Pharmacy; Physical Sciences; Protein folding; Science & Technology; Structure-Activity Relationship; tau Proteins - antagonists & inhibitors; tau Proteins - metabolism; Tauopathy; Thiazolidines - chemical synthesis; Thiazolidines - chemistry; Thiazolidines - pharmacology; Neurodegeneration; Protein folding; Tauopathy; Metabolism; Hsp72; Hsc70; Molecular chaperone; COMPLEX; TURNOVER; ACETYLATION; DRUG DISCOVERY; MKT-077; MODULATION
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128025

[Display omitted] •Two series of YM-08 analogs were designed to remove metabolic liabilities.•Optimization resulted in JG-23, which is 12-fold more metabolically stable.•Compound JG-23 reduced total tau in two cell-based models. 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.