Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors

Byrd, Katherine M.; Subramanian, Chitra; Sánchez, Jacqueline; Motiwala, Hashim F.; Liu, Weiya; Cohen, Mark S.; Holzbeierlein, Jeffrey M.; Blagg, Brian S. J.

doi:10.1002/chem.201504955

Cited by 38 publications

(33 citation statements)

References 53 publications

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“…[14a, 17] In addition, it was determined that the planarity and flexibility of the central core are important for Hsp90 inhibitory activity. [15] Therefore, it was hypothesized that the central core could be modified to optimize orientation of the side chains for increased inhibitory activity. Since biphenyl analogues manifest superior activity, this scaffold was chosen as the starting point for the discovery of more efficacious Hsp90 inhibitors.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have suggested that an optimal distance between 7.7 and 12.1 Å from the amine to the amide is important for Hsp90 inhibitory activity. [15] Therefore, analogues containing five-, six- and seven-membered rings with varying distances and orientations of both the amine and amide were pursued.…”

Section: Resultsmentioning

confidence: 99%

“…[14] More recently, we demonstrated that a stilbene core (Figure 1) could be used in lieu of the coumarin core as well. [15] In continuation of these studies, the current work identifies a novel core, which has led to the development of more efficacious Hsp90 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C‐terminal Inhibitors

Garg

Forsberg

Zhao

et al. 2017

Chemistry A European J

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Inhibition of the heat shock protein 90 (Hsp90) C-terminus represents a promising therapeutic strategy for the treatment of cancer. Novobiocin, a coumarin antibiotic, was the first Hsp90 C-terminal inhibitor identified, however, it manifested poor anti-proliferative activity (SKBr3, IC50 ~ 700 μM). Subsequent SAR studies on novobiocin led to development of several analogues that exhibited improved anti-proliferative activity against several cancer cell lines. Recently, we demonstrated that the biphenyl core could be used in lieu of the coumarin ring system, which resulted in more efficacious analogues. In continuation of previous efforts, the work described herein has identified the phenyl cyclohexyl core as a novel scaffold for Hsp90 C-terminal inhibition. SAR studies on this scaffold led to the development of compounds that manifest mid-nanomolar activity against SKBr3 and MCF-7 breast cancer cell lines through Hsp90 inhibition.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C‐terminal Inhibitors

Garg

Forsberg

Zhao

et al. 2017

Chemistry A European J

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“…The results indicated that NOVO exhibited similar effects as the TRPV1 specific inhibitor SB-705498 in inhibiting the accumulation of CAP after pre-incubation for 24 h. Thus, the reason why the permeability of CAP decreased was that NOVO inhibited the expression of TRPV1. It is known that NOVO is a DNA gyrase inhibitor, and it has been shown that NOVO can affect the regulation of the transcription and translation of many genes ( Gmuender et al, 2001 ; Chatt et al, 2014 ; Byrd et al, 2016 ). Therefore, decreased TRPV1 expression may be regulated by one of the genes that are affected by NOVO.…”

Section: Discussionmentioning

confidence: 99%

Novobiocin, a Newly Found TRPV1 Inhibitor, Attenuates the Expression of TRPV1 in Rat Intestine and Intestinal Epithelial Cell Line IEC-6

Liang

Cai

et al. 2018

Front. Pharmacol.

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Background and Purpose: Novobiocin (NOVO), an ABC transporter inhibitor, decreases intestinal wall permeability of capsaicin (CAP), an ABC transporter substrate. However, the mechanism of this effect is not consistent with the action of NOVO as an ABC transporter inhibitor. We previously found that CAP can also be transported via TRPV1, which was site-specific in the permeability of CAP across the intestine. We explored the regulation by NOVO of TRPV1 in the present study.Methods: Rats and transfected IEC-6 cells were used as the models to assess intestinal permeability and expression of TRPV1. Ussing chamber and intracellular accumulation were used to evaluate the influence of NOVO on the transport of CAP in vitro. The expression of TRPV1 was detected after administration of NOVO by qRT-PCR, western blot and immunofluorescent imaging. In addition, MTT and lactate dehydrogenase (LDH) were used to evaluate the cytotoxicity of NOVO in both rat and cell models. Finally, the effect of NOVO on the absorption of CAP in vivo was studied by LC-MS/MS.Results: In vitro data showed that there existed a dose-dependent relationship in the range of concentration between 5 and 50 μM, and even 5 μM NOVO could decrease intestinal permeability of CAP across the intestine. Meanwhile, cytosolic accumulation of CAP decreased when NOVO was used simultaneously or 24 h in advance. NOVO exhibited an inhibition level similar to that of ruthenium red (RR) or SB-705498, a TRPV1-specific inhibitor. NOVO down-regulated TRPV1 expression in the intestine and in transfected cells in a concentration-dependent fashion, hinting that its inhibition of the permeability of CAP is due to its inhibition of TRPV1 expression. Immunofluorescent imaging data showed that the fluorescence intensity of TRPV1 was reduced after pre-treatment with NOVO and SB-705498. In vivo data further demonstrated that oral co-administration of NOVO decreased Cmax and AUC of CAP in dosage-dependent ways, consistent with its role as a TRPV1 inhibitor.Conclusion: NOVO could be a potential TRPV1 inhibitor by attenuating the expression of TRPV1 and may be used to attenuate permeability of TRPV1 substrates.

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“…In the LB model, the aromatic feature is in closer proximity to the positive ionizable (6.45 Å) than in the SB-model, where it is positioned near the H-bond donor. The optimal distance and angle between the N-methylpiperidine and the biaryl side chain have been studied in a library of novobiocin core analogs [31]. The resulting LB model based on some of those optimized structures reflects both features.…”

Section: Comparison Of Lb and Md-derived Sb Modelsmentioning

confidence: 99%

Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations

Tomašič

Durcik

Keegan

et al. 2020

IJMS

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Hsp90 C-terminal domain (CTD) inhibitors are promising novel agents for cancer treatment, as they do not induce the heat shock response associated with Hsp90 N-terminal inhibitors. One challenge associated with CTD inhibitors is the lack of a co-crystallized complex, requiring the use of predicted allosteric apo pocket, limiting structure-based (SB) design approaches. To address this, a unique approach that enables the derivation and analysis of interactions between ligands and proteins from molecular dynamics (MD) trajectories was used to derive pharmacophore models for virtual screening (VS) and identify suitable binding sites for SB design. Furthermore, ligand-based (LB) pharmacophores were developed using a set of CTD inhibitors to compare VS performance with the MD derived models. Virtual hits identified by VS with both SB and LB models were tested for antiproliferative activity. Compounds 9 and 11 displayed antiproliferative activities in MCF-7 and Hep G2 cancer cell lines. Compound 11 inhibited Hsp90-dependent refolding of denatured luciferase and induced the degradation of Hsp90 clients without the concomitant induction of Hsp70 levels. Furthermore, compound 11 offers a unique scaffold that is promising for the further synthetic optimization and development of molecules needed for the evaluation of the Hsp90 CTD as a target for the development of anticancer drugs.

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Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors

Cited by 38 publications

References 53 publications

Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C‐terminal Inhibitors

Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C‐terminal Inhibitors

Novobiocin, a Newly Found TRPV1 Inhibitor, Attenuates the Expression of TRPV1 in Rat Intestine and Intestinal Epithelial Cell Line IEC-6

Discovery of Novel Hsp90 C-Terminal Inhibitors Using 3D-Pharmacophores Derived from Molecular Dynamics Simulations

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