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From Bacteria to Cancer: A Benzothiazole-Based DNA Gyrase B Inhibitor Redesigned for Hsp90 C‑Terminal Inhibition
journal contribution
posted on 2020-07-01, 11:42 authored by Kyler
W. Pugh, Zheng Zhang, Jian Wang, Xiuzhi Xu, Vitumbiko Munthali, Ang Zuo, Brian S. J. BlaggHeat
shock protein 90 (Hsp90) is a molecular chaperone that is
responsible for the folding and maturation of client proteins that
are associated with all ten hallmarks of cancer. Hsp90 N-terminal
pan inhibitors have experienced unfavorable results in clinical trials
due to induction of the heat shock response (HSR), among other concerns.
Novobiocin, a well characterized DNA gyrase B inhibitor, was identified
as the first Hsp90 C-terminal inhibitor that manifested anticancer
effects without induction of the HSR. In this letter, a library of
Hsp90 C-terminal inhibitors derived from a benzothiazole-based scaffold,
known to inhibit DNA gyrase B, was designed, synthesized, and evaluated.
Several compounds were found to manifest low micromolar activity against
both MCF-7 and SKBr3 breast cancer cell lines via Hsp90 C-terminal
inhibition.
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DNA gyrase B inhibitorMCF -7DNA gyrase BHsp 90 C-terminal inhibitorsHSRclient proteinsHsp 90 C-terminal inhibitionbenzothiazole-based scaffoldmicromolar activityheat shock responseBenzothiazole-Based DNA Gyrase B In...Hsp 90 C-terminal inhibitorSeveral compoundsanticancer effectsSKBr 3 breast cancer cell linesHsp 90 N-terminal pan inhibitors
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