2. Academic Validation
  3. Inhibitors of heat shock protein 70 (Hsp70) with enhanced metabolic stability reduce tau levels

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

  • Bioorg Med Chem Lett. 2021 Jun 1;41:128025. doi: 10.1016/j.bmcl.2021.128025.
Hao Shao 1,  Xiaokai Li 2,  Shigenari Hayashi 3,  Jeanette L Bertron 2,  Daniel M C Schwarz 2,  Benjamin C Tang 3,  Jason E Gestwicki 4
Affiliations

Affiliations

  • 1 Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China. Electronic address: [email protected].
  • 2 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.
  • 3 Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA 94158, United States.
  • 4 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. Electronic address: [email protected].
PMID: 33839251 DOI: 10.1016/j.bmcl.2021.128025
Abstract

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.

Keywords

Hsc70; Hsp72; Metabolism; Molecular chaperone; Neurodegeneration; Protein folding; Tauopathy.

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