Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy

Porter, James R.; Fritz, Christian; Depew, Kristopher M.

doi:10.1016/j.cbpa.2010.03.019

Cited by 167 publications

(159 citation statements)

References 61 publications

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“…To date, there are 13 new Hsp90 inhibitors at various stages of clinical development (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). The earlier geldanamycin analogues (i.e., 17-AAG or 17-DMAG), despite potent in vitro and in vivo preclinical activity, have not shown clear clinical benefit (5,31).…”

Section: Discussionmentioning

confidence: 99%

“…NVP-HSP990 is highly potent and selective for Hsp90 and represents one of the most potent oral Hsp90 inhibitors reported (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). The GTL-16 model was selected as a screening model due to its growth and survival dependency on the Hsp90 client protein c-Met (24).…”

Section: Discussionmentioning

confidence: 99%

“…Hsp90 inhibition destabilizes diverse oncoproteins, resulting in simultaneous blockade of multiple tumorigenic signaling pathways, arrest of cell proliferation, and induction of apoptosis (3,4). Because of the potential therapeutic use in multiple cancer indications, several Hsp90 inhibitors have been identified and are being evaluated as anticancer drugs (3,(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

“…Currently, 13 synthetic Hsp90 inhibitors are under assessment in oncology clinical trials. Six inhibitors (IPI-504, NVP-AUY922, KW-2478, STA-9090, AT13387, and BIIB-028) are administered intravenously, whereas 7 (BIIB-021, IPI-493, XL-888, MPC-3100, DS-2248, Debio 0932, and NVP-HSP990) are dosed orally (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). These inhibitors address some key pharmaceutical limitations of 17-AAG (5-7).…”

Section: Introductionmentioning

confidence: 99%

“…All other Hsp90 inhibitors are fully synthetic small molecules that fall into distinct structural classes including: (i) resorcinol-containing molecules (NVP-AUY922, KW-2478, STA-9090, and AT13387), (ii) purine scaffold (BIIB021, PU-H71, and MPC-3100), (iii) imidazopyridine (Debio 0932), (iv) 2-aminoterephthalamide (XL888), and (v) aminopyrimidine (NVP-HSP990). The chemical structures of BIIB028 and DS- 2248 have not yet been disclosed (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Menezes

Taverna

Jensen

et al. 2012

Molecular Cancer Therapeutics

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A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC 50 values on three of the Hsp90 isoforms (Hsp90a, Hsp90b, and GRP94) and 320 nanomolar IC 50 value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Menezes

Taverna

Jensen

et al. 2012

Molecular Cancer Therapeutics

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Pharmacologic heat shock protein 70 induction confers cytoprotection against inflammation in gliovascular cells

Kacimi

Yenari

2015

Glia

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Inhibition of the 90 kDa heat-shock protein (HSP90) leads to upregulation of the 70 kDa inducible heat shock protein (HSP70). HSP70 has previously been shown to be neuroprotective and anti-inflammatory. Geldanamycin (GA) and other HSP90 inhibitors have emerged as promising therapeutic agents in cancer, presumably due to their ability to upregulate HSP70. However, the effects of HSP90 inhibition in brain inflammation are still unclear. We investigate the effect of a panel of HSP90 inhibitors on endotoxin-activated microglia and eventual protection from brain derived endothelial cells. Prior studies have shown that GA protects brain cells from oxidative stress. We show here that when astrocytes or microglial BV2 cells were pretreated with GA or other HSP90 inhibitors, endotoxin-induced cell death was reduced in co-cultures of BV2 microglia and brain derived endothelial cells (bEND.3). Endotoxin stimulated BV2 cells led to increased nitric oxide (NO) and inducible nitric oxide synthase (iNOS) which was prevented by treatment with all HSP90 inhibitors. HSP90 inhibitors also prevented LPS -induced BV2 cell death. We also found that HSP90 inhibition blocked nuclear translocation of NF-κB and attenuated IκBα degradation, and inhibited LPS-activated JAK-STAT phosphorylation. We show that pharmacologic inhibition of HSP90 with subsequent HSP70 induction protects cells that comprise the cerebral vasculature against cell death due to pro-inflammatory stimuli. This approach may have therapeutic potential in neurological conditions with an inflammatory component.

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Computational Studies of Allosteric Regulation in the Hsp90 Molecular Chaperone: From Functional Dynamics and Protein Structure Networks to Allosteric Communications and Targeted Anti‐Cancer Modulators

Verkhivker¹

2014

Israel Journal of Chemistry

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Computational studies of allosteric interactions have witnessed a recent renaissance fueled by growing interest in the modeling of complex molecular assemblies and biological networks. Allosteric interactions of the molecular chaperone Hsp90 with a diverse array of cochaperones and client proteins allow for molecular communication in signal transduction networks. In this review, recent developments in the understanding of allosteric interactions in the context of structural, functional, and computational studies of the Hsp90 chaperone are discussed. A comprehensive analysis of structural and network‐based models of protein allostery is provided. Computational and experimental approaches and advances in the understanding of Hsp90 interactions and regulatory mechanisms are reviewed to provide a systematic and critical view of the current progress and most challenging questions in the field. The current status and future prospects for translational research, bridging the basic science of chaperones with the discovery of anti‐cancer therapies, are also highlighted.

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Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy

Cited by 167 publications

References 61 publications

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Pharmacologic heat shock protein 70 induction confers cytoprotection against inflammation in gliovascular cells

Computational Studies of Allosteric Regulation in the Hsp90 Molecular Chaperone: From Functional Dynamics and Protein Structure Networks to Allosteric Communications and Targeted Anti‐Cancer Modulators

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