Hsp90: Friends, clients and natural foes

Verma, Subhash; Goyal, Sukriti; Jamal, Salma; Singh, Aditi; Grover, Abhinav

doi:10.1016/j.biochi.2016.05.018

Cited by 77 publications

(56 citation statements)

References 209 publications

(126 reference statements)

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“…Therefore, our present findings, showing that HSP90 inhibitors could function as an up-regulator with regard to the PGF 2α -stimulated IL-6 synthesis in osteoblasts, probably provides a novel insight with regard to HSP90 as an essential regulator of bone remodeling. Several HSP90 inhibitors including geldanamycin have been recognized as an anticancer drug, and the effects of HSP90 inhibitors have been tested in the clinical trial [38]. Based on our present findings, it is probable that HSP90 inhibitors, in addition to the anticancer chemotherapeutics, could affect bone metabolism as a bone remodeling modulator through the enhancement of IL-6 synthesis in osteoblasts.…”

Section: Discussionmentioning

confidence: 62%

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

et al. 2017

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Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F2α (PGF2α), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that Rho-kinase acts at a point upstream of p38 MAP kinase. In the present study, we investigated the involvement of HSP90 in the PGF2α-stimulated IL-6 synthesis and the underlying mechanism in MC3T3-E1 cells. Geldanamycin, an inhibitor of HSP90, significantly amplified both the PGF2α-stimulated IL-6 release and the mRNA expression levels. In addition, other HSP90 inhibitors, 17-allylamino-17demethoxy-geldanamycin (17-AAG) and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib, enhanced the PGF2α-stimulated IL-6 release. Geldanamycin, 17-AAG and onalespib markedly strengthened the PGF2α-induced phosphorylation of p38 MAP kinase. Geldanamycin and 17-AAG did not affect the PGF2α-induced phosphorylation of p44/p42 MAP kinase and myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase, and the protein levels of RhoA and Rho-kinase. In addition, HSP90-siRNA enhanced the PGF2α-induced phosphorylation of p38 MAP kinase. Furthermore, SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by geldanamycin, 17-AAG or 17-DMAG of the PGF2α-stimulated IL-6 release. Our results strongly suggest that HSP90 negatively regulates the PGF2α-stimulated IL-6 synthesis in osteoblasts, and that the effect of HSP90 is exerted through regulating p38 MAP kinase activation.

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Section: Discussionmentioning

confidence: 62%

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

et al. 2017

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“…45–47 Curiously, the inhibitors discovered by Abbott and Biogen bound to the catalytic D93 of mammalian HSP90 through the aminopyrimidine moiety, a position equivalent to 2-C of adenine (Figure 6b). 45,48 Importantly, similar compounds from our library ( 13 , 14 , 20 , 21 ) showed negligible activity, with the exception of 19 .…”

Section: Resultsmentioning

confidence: 99%

Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases

2017

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Bacterial histidine kinases (HKs) are quintessential regulatory enzymes found ubiquitously in bacteria. Apart from their regulatory roles, they are also involved in the production of virulence factors and conferring resistance to various antibiotics in pathogenic microbes. We have previously reported compounds that inhibit multiple HKs by targeting the conserved catalytic and ATP-binding (CA) domain. Herein, we conduct a detailed structure–activity relationship assessment of adenine-based inhibitors using biochemical and docking methods. These studies have resulted in several observations. First, interaction of an inhibitor’s amine group with the conserved active-site Asp is essential for activity and likely dictates its orientation in the binding pocket. Second, a N-NH-N triad in the inhibitor scaffold is highly preferred for binding to conserved Gly:Asp:Asn residues. Lastly, hydrophobic electron-withdrawing groups at several positions in the adenine core enhance potency. The selectivity of these inhibitors was tested against heat shock protein 90 (HSP90), which possesses a similar ATP-binding fold. We found that groups that target the ATP-lid portion of the catalytic domain, such as a six-membered ring, confer selectivity for HKs.

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“…462,463 Because many Hsp90 client proteins are in oncogenic signaling pathways, Hsp90 was proposed as a therapeutic target for anticancer strategies. 464 Geldanamycin is a naturally occurring antibiotic, with Hsp90 identified as its molecular target.…”

Section: Mitochondria-targeted Bioactive Compounds As Potential Thmentioning

confidence: 99%

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

Zielonka¹,

Joseph²,

et al. 2017

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Mitochondria are recognized as one of the most important targets for new drug design in cancer, cardiovascular, and neurological diseases. Currently, the most effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest. Other delocalized lipophilic cations, such as rhodamine, natural and synthetic mitochondria-targeting peptides, and nanoparticle vehicles, have also been used for mitochondrial delivery of small molecules. Depending on the approach used, and the potentials of cell and mitochondrial membranes, more than 1000-fold higher mitochondrial concentration can be achieved. Mitochondrial targeting has been developed to study mitochondrial physiology and dysfunction and the interaction between mitochondria and other subcellular organelles and for treatment of a variety of diseases such as neurodegeneration and cancer. In this review, we discuss efforts to target small-molecule compounds to mitochondria for probing mitochondria function, as diagnostic tools and potential therapeutics. We describe the physicochemical basis for mitochondrial accumulation of lipophilic cations, synthetic chemistry strategies to target compounds to mitochondria, mitochondrial probes and sensors, and examples of mitochondrial targeting of bioactive compounds. Finally, we review published attempts to apply mitochondria-targeted agents for the treatment of cancer and neurodegenerative diseases.

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Hsp90: Friends, clients and natural foes

Cited by 77 publications

References 209 publications

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

HSP90 inhibitors potentiate PGF2α-induced IL-6 synthesis via p38 MAP kinase in osteoblasts

Rational Design of Selective Adenine-Based Scaffolds for Inactivation of Bacterial Histidine Kinases

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

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