biostudies-literature00610Shao HNational Institute of Neurological Disorders and StrokeTau ConsortiumNCI NIH HHSNINDS NIH HHS6163-6177https://www.ebi.ac.uk/biostudies/studies/S-EPMC6104643biostudies-literatureUnknown61(14)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.Journal of medicinal chemistryExploration of Benzothiazole Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70).PMC6104643R00 CA204602U54 CA196519R01 NS059690R01NS059690Gilbert LAChernova MShao HYoung ZTJacobson MPNeckers LJourney SNWeissman JSKalyanaraman CLi XGestwicki JEMoses MAHann B61falseExploration of Benzothiazole Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70).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.2018-01-01T00:00:00Z2018 Jul2024-11-13T08:22:40.677Z2019-07-30T07:00:55ZS-EPMC61046432995380810.1021/acs.jmedchem.8b00583