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From Bacteria to Cancer: A Benzothiazole-Based DNA Gyrase B Inhibitor Redesigned for Hsp90 C-Terminal Inhibition.

ABSTRACT: Heat 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.

SUBMITTER: Pugh KW

PROVIDER: S-EPMC7429967 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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From Bacteria to Cancer: A Benzothiazole-Based DNA Gyrase B Inhibitor Redesigned for Hsp90 C-Terminal Inhibition.

Pugh Kyler W KW Zhang Zheng Z Wang Jian J Xu Xiuzhi X Munthali Vitumbiko V Zuo Ang A Blagg Brian S J BSJ

ACS medicinal chemistry letters 20200611 8

Heat 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 induc ...[more]

PMID: 32832020

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