2182-74-3Relevant academic research and scientific papers
Tunable Heteroaromatic Sulfones Enhance in-Cell Cysteine Profiling
Motiwala, Hashim F.,Kuo, Yu-Hsuan,Stinger, Brittany L.,Palfey, Bruce A.,Martin, Brent R.
supporting information, p. 1801 - 1810 (2020/02/04)
Heteroaromatic sulfones react with cysteine via nucleophilic aromatic substitution, providing a mechanistically selective and irreversible scaffold for cysteine conjugation. Here we evaluate a library of heteroaromatic sulfides with different oxidation st
Exploration of Benzothiazole Rhodacyanines as Allosteric Inhibitors of Protein-Protein Interactions with Heat Shock Protein 70 (Hsp70)
Shao, Hao,Li, Xiaokai,Moses, Michael A.,Gilbert, Luke A.,Kalyanaraman, Chakrapani,Young, Zapporah T.,Chernova, Margarita,Journey, Sara N.,Weissman, Jonathan S.,Hann, Byron,Jacobson, Matthew P.,Neckers, Len,Gestwicki, Jason E.
, p. 6163 - 6177 (2018/07/09)
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.
Analogues of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents
Li, Xiaokai,Srinivasan, Sharan R.,Connarn, Jamie,Ahmad, Atta,Young, Zapporah T.,Kabza, Adam M.,Zuiderweg, Erik. R. P.,Sun, Duxin,Gestwicki, Jason E.
, p. 1042 - 1047 (2013/12/04)
The rhodacyanine, MKT-077, has antiproliferative activity against cancer cell lines through its ability to inhibit members of the heat shock protein 70 (Hsp70) family of molecular chaperones. However, MKT-077 is rapidly metabolized, which limits its use as either a chemical probe or potential therapeutic. We report the synthesis and characterization of MKT-077 analogues designed for greater stability. The most potent molecules, such as 30 (JG-98), were at least 3-fold more active than MKT-077 against the breast cancer cell lines MDA-MB-231 and MCF-7 (EC50 values of 0.4 ± 0.03 and 0.7 ± 0.2 μM, respectively). The analogues modestly destabilized the chaperone clients, Akt1 and Raf1, and induced apoptosis in these cells. Further, the microsomal half-life of JG-98 was improved at least 7-fold (t1/2 = 37 min) compared to MKT-077 (t1/2 5 min). Finally, NMR titration experiments suggested that these analogues bind an allosteric site that is known to accommodate MKT-077. These studies advance MKT-077 analogues as chemical probes for studying Hsp70s roles in cancer.
