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

Pugh, Kyler W; Zhang, Zheng; Wang, Jian; Xu, Xing‐You; Munthali, Vitumbiko; Zuo, Ang; Blagg, Brian S. J.

doi:10.1021/acsmedchemlett.0c00100

Cited by 22 publications

(15 citation statements)

References 17 publications

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“…On the contrary, a known Hsp90 NTD inhibitor 17-DMAG that was used as a positive control resulted in significant upregulation of these heat shock proteins. These data confirmed that this new class of inhibitor modulates the activity of Hsp90 in a CTD allosteric manner, similar to the previously reported benzothiazole-based CTD inhibitors [ 35 ].…”

Section: Resultssupporting

confidence: 90%

“…The benzothiazole moiety was selected as a suitable central scaffold that offers the possibility for the attachment of aromatic substituents and basic amines to positions 2 and 6, which are characteristic for Hsp90 CTD inhibitors ( Figure 1 ). In contrast to the already known benzothiazoles A and B ( Figure 2 ) [ 34 , 35 ], we decided to introduce aromatic groups at position 6 of the benzothiazole moiety and to replace the amide bond at position 2 with an amine directly linked to the benzothiazole ring ( Figure 2 ). This amine would serve as an attachment point for the various linkers to the basic center.…”

Section: Resultsmentioning

confidence: 99%

“…This amine would serve as an attachment point for the various linkers to the basic center. Furthermore, a different orientation of the amide bond was introduced at position 6, in contrast to the already known inhibitors [ 34 , 35 ].…”

Section: Resultsmentioning

confidence: 99%

“…First, the importance of the cationic center in the compounds was evaluated. This was because the previously developed benzothiazole-based Hsp90 CTD inhibitors did not contain a cationic center in their structure [ 34 , 35 ]. For this purpose, variously substituted piperidines were introduced at position 2 of the benzothiazole ring.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, a structure-based study using the cryo-electron microscopy structure of Hsp90β confirmed the importance of the basic center and the aromatic ring at the appropriate distance [ 32 ]. On the other hand, the benzothiazole has been shown to be a useful structural feature for Hsp90 inhibitors [ 34 ] that target the CTD [ 35 ]. However, no connections between the CTD SARs and the benzothiazole ring as a central scaffold have been established to date.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

et al. 2021

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Heat shock protein 90 (Hsp90) is a chaperone responsible for the maturation of many cancer-related proteins, and is therefore an important target for the design of new anticancer agents. Several Hsp90 N-terminal domain inhibitors have been evaluated in clinical trials, but none have been approved as cancer therapies. This is partly due to induction of the heat shock response, which can be avoided using Hsp90 C-terminal-domain (CTD) inhibition. Several structural features have been shown to be useful in the design of Hsp90 CTD inhibitors, including an aromatic ring, a cationic center and the benzothiazole moiety. This study established a previously unknown link between these structural motifs. Using ligand-based design methodologies and structure-based pharmacophore models, a library of 29 benzothiazole-based Hsp90 CTD inhibitors was prepared, and their antiproliferative activities were evaluated in MCF-7 breast cancer cells. Several showed low-micromolar IC50, with the most potent being compounds 5g and 9i (IC50, 2.8 ± 0.1, 3.9 ± 0.1 μM, respectively). Based on these results, a ligand-based structure–activity relationship model was built, and molecular dynamics simulation was performed to elaborate the binding mode of compound 9i. Moreover, compound 9i showed degradation of Hsp90 client proteins and no induction of the heat shock response.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

et al. 2021

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Benzothiazole derivatives in the design of antitumor agents

Paoletti,

Supuran

2024

Archiv der Pharmazie

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Benzothiazoles are a class of heterocycles with multiple applications as anticancer, antibiotic, antiviral, and anti‐inflammatory agents. Benzothiazole is a privileged scaffold in drug discovery programs for modulating a variety of biological functions. This review focuses on the design and synthesis of new benzothiazole derivatives targeting hypoxic tumors. Cancer is a major health problem, being among the leading causes of death. Tumor‐hypoxic areas promote proliferation, malignancy, and resistance to drug treatment, leading to the dysregulation of key signaling pathways that involve drug targets such as vascular endothelial growth factor, epidermal growth factor receptor, hepatocyte growth factor receptor, dual‐specificity protein kinase, cyclin‐dependent protein kinases, casein kinase 2, Rho‐related coil formation protein kinase, tunica interna endothelial cell kinase, cyclooxygenase‐2, adenosine kinase, lysophosphatidic acid acyltransferases, stearoyl‐CoA desaturase, peroxisome proliferator‐activated receptors, thioredoxin, heat shock proteins, and carbonic anhydrase IX/XII. In turn, they regulate angiogenesis, proliferation, differentiation, and cell survival, controlling the cell cycle, inflammation, the immune system, and metabolic alterations. A wide diversity of benzothiazoles were reported over the last years to interfere with various proteins involved in tumorigenesis and, more specifically, in hypoxic tumors. Many hypoxic targets are overexpressed as a result of the hypoxia‐inducible factor activation cascade and may not be present in normal tissues, providing a potential strategy for selectively targeting hypoxic cancers.

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Synthesis of C3′‐Foused Aryl/Penta‐1,4‐Dien‐3‐One/Amine Hybrids as HSP90C‐Terminal Inhibitors

Zheng,

Liao,

Wang

et al. 2024

Chemistry & Biodiversity

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24 C3′‐focused hybrids of aryl/penta‐1,4‐dien‐3‐one/amine (APDA) were designed and synthesized. Of these hybrids, 2n demonstrated improved antiproliferative effects on HER2‐positive breast cancer cells (SKBr3 and BT474) and triple‐negative breast cancer (TNBC) cells (MDA‐MB‐231 and MDA‐MB‐468) with IC50 values ranging from 7.45 to 10.75 μM, but less toxicity to normal breast cells MCF‐10A than the first generation of hybrid 1. Additionally, 2n retained its ability to inhibit HSP90 C‐terminus, leading to the degradation of HSP90 client proteins HER2, EGFR, pAKT, AKT, and CDK4, without inducing a heat‐shock response. Notably, 2n also demonstrated improved thermostability compared to 1 and maintained in vitro metabolic stability in simulated intestinal fluid. These findings will provide a scientific basis for developing HSP90 C‐terminal inhibitors in the future.

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

Cited by 22 publications

References 17 publications

Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

Structure-Activity Relationships of Benzothiazole-Based Hsp90 C-Terminal-Domain Inhibitors

Benzothiazole derivatives in the design of antitumor agents

Synthesis of C3′‐Foused Aryl/Penta‐1,4‐Dien‐3‐One/Amine Hybrids as HSP90C‐Terminal Inhibitors

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