Neutral analogs of the heat shock protein 70 (Hsp70) inhibitor,JG-98 |
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| Affiliation: | 3. From the Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158;4. Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109;3. From the Department of Molecular Medicine, College of Medicine, USF Health Byrd Alzheimer''s Institute, University of South Florida, Tampa, Florida 33613;4. James A. Haley Veteran''s Hospital, Tampa, Florida 33612;5. Deparment of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, Florida 33620;6. Institute for Neurodegenerative Disease, University of California, San Francisco, California 94158;12. Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109;1. National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China;2. University of the Chinese Academy of Sciences, Beijing, China;1. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, PO Box 210207, Tucson, AZ 85721, USA;2. Indiana University, School of Medicine, Department of Biochemistry and Molecular Biology, 635 Barnhill Dr., Indianapolis, IN 46202, USA |
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| 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. |
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| Keywords: | Allosteric inhibitor Molecular chaperone Proteostasis Prostate cancer Breast cancer Chemical probe Anti-cancer agents Fluorescence |
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