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J Med Chem. 2018 Jul 26;61(14):6163-6177. doi: 10.1021/acs.jmedchem.8b00583. Epub 2018 Jul 13.

Exploration of Benzothiazole Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70).

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Department of Pharmaceutical Chemistry , University of California at San Francisco , Sandler Center, 675 Nelson Rising Lane , San Francisco , California 94158 , United States.
Urologic Oncology Branch, Center for Cancer Research , National Cancer Institute , Bethesda , Maryland 20892 , United States.
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute , University of California at San Francisco , San Francisco , California 94158 , United States.
Helen Diller Family Comprehensive Cancer Centre and Preclinical Therapeutics Core , University of California at San Francisco , San Francisco , California 94158 , United States.


Cancer cells rely on the chaperone heat shock protein 70 (Hsp70) for survival and proliferation. Recently, benzothiazole rhodacyanines have been shown to bind an allosteric site on Hsp70, interrupting its binding to nucleotide-exchange factors (NEFs) and promoting cell death in breast cancer cell lines. However, proof-of-concept molecules, such as JG-98, have relatively modest potency (EC50 ≈ 0.7-0.4 μM) and are rapidly metabolized in animals. Here, we explored this chemical series through structure- and property-based design of ∼300 analogs, showing that the most potent had >10-fold improved EC50 values (∼0.05 to 0.03 μM) against two breast cancer cells. Biomarkers and whole genome CRISPRi screens confirmed members of the Hsp70 family as cellular targets. On the basis of these results, JG-231 was found to reduce tumor burden in an MDA-MB-231 xenograft model (4 mg/kg, ip). Together, these studies support the hypothesis that Hsp70 may be a promising target for anticancer therapeutics.

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