2. Academic Validation
  3. Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98

Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor, JG-98

  • Bioorg Med Chem Lett. 2020 Mar 1;30(5):126954. doi: 10.1016/j.bmcl.2020.126954.
Hao Shao 1,  Jason E Gestwicki 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA.
  • 2 Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].
PMID: 31952963 DOI: 10.1016/j.bmcl.2020.126954
Abstract

The heat shock protein 70 (HSP70) family of molecular chaperones are highly expressed in tumors. Inhibitors containing a pyridinium-modified benzothiazole, such as JG-98, bind to a conserved, allosteric site in HSP70, showing promising anti-proliferative activity in Cancer cells. When bound to HSP70, the charged pyridinium makes favorable contacts; however, this moiety also increases the inhibitor's fluorescence, giving rise to undesirable interference in biochemical and cell-based assays. Here, we explore whether the pyridinium can be replaced with a neutral pyridine. We report that pyridine-modified benzothiazoles, such as compound 17h (JG2-38), have reduced fluorescence, yet retain promising anti-proliferative activity (EC50 values ~0.1 to 0.07 µM) in breast and prostate Cancer cell lines. These chemical probes are expected to be useful in exploring the roles of Hsp70s in tumorigenesis and cell survival.

Keywords

Allosteric inhibitor; Anti-cancer agents; Breast cancer; Chemical probe; Fluorescence; Molecular chaperone; Prostate cancer; Proteostasis.

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