Heat-shock protein 90, a chaperone for folding and regulation

Picard, Didier

doi:10.1007/pl00012491

Cited by 733 publications

(610 citation statements)

References 117 publications

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“…Hsp90 also plays key roles in regulating protein function and stability in normal cells (21). Therefore, balancing efficacy and toxicity is essential to achieving a suitable therapeutic index in patients.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Since unicellular parasites are exposed to extreme changes in their environment as they cycle between host and vector, their heat-shock proteins may play an important role. The molecular chaperone Hsp90 has been shown to be essential for viability in organisms ranging from yeast to mouse [1][2][3]. The life cycle of Pf has been shown to be blocked in vitro with two chemically distinct Hsp90 inhibitors, radicicol (Rd) and geldanamycin (GA), primarily at the transition from the Ring to the trophozoite stage in erythrocytes [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Wider

Péli-Gulli

Briand

et al. 2009

Molecular and Biochemical Parasitology

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Developing novel drugs against the unicellular parasite Plasmodium is complicated by the paucity of simple screening systems. Heat-shock proteins are an essential class of proteins for the parasite's cyclical life style between different cellular milieus and temperatures. The molecular chaperone Hsp90 assists a large variety of proteins, but its supporting functions for many proteins that are important for cancer have made it into a well-studied drug target. With a better understanding of the differences between Hsp90 of the malarial parasite and Hsp90 of its human host, new therapeutic options might become available. We have generated a set of isogenic strains of the budding yeast Saccharomyces cerevisiae where the essential yeast Hsp90 proteins have been replaced with either of the two human cytosolic isoforms Hsp90α or Hsp90β, or with Hsp90 from Plasmodium falciparum (Pf). All strains express large amounts of the Flag-tagged Hsp90 proteins and are viable. Even though the strain with Pf Hsp90 grows more poorly, it provides a tool to reconstitute additional aspects of the parasite Hsp90 complex and its interactions with substrates in yeast as a living test tube. Upon exposure of the set of Hsp90 test strains to the two Hsp90 inhibitors radicicol (Rd) and geldanamycin (GA), we found that the strain with Pf Hsp90 is relatively more sensitive to GA than to Rd compared to the strains with human Hsp90's. This indicates that this set of yeast strains could be used to screen for new Pf Hsp90 inhibitors with a wider therapeutic window

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“…[1][2][3][4]. Despite over a decade of intense study, the basis for the recognition by Hsp90 of its diverse clients remains one of the primary mysteries in the field.…”

mentioning

confidence: 99%

“…[1][2][3][4]. Current models suggest that co-chaperones may confer specificity to Hsp90 facilitated protein folding by also interacting with client targets (5,13,14).…”

mentioning

confidence: 99%

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Definition of Protein Kinase Sequence Motifs That Trigger High Affinity Binding of Hsp90 and Cdc37

Prince

Matts

2004

Journal of Biological Chemistry

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Hsp90 cooperates with its co-chaperone Cdc37 to provide obligatory support to numerous protein kinases involved in the regulation of cellular signal transduction pathways. In this report, the crystal structure of the Src family tyrosine kinase Lck was used to guide the creation of kinase constructs to determine features recognized by Hsp90 and its "kinase-specific" co-chaperone Cdc37. Two parameters were assayed: the ability and extent to which the constructs bound to Hsp90 and Cdc37, and the ability of the constructs to trigger saltresistant high affinity complexes with Hsp90 and Cdc37 independent of the presence of molybdate. Although Hsp90 interacted with both the N-terminal and C-terminal lobes (NL and CL, respectively) of the catalytic domains of the kinases, the lobes themselves were not sufficient to trigger the high affinity binding of Hsp90. Only constructs containing a complete N-or C-terminal lobe and part of the adjacent lobe bound to Hsp90 and Cdc37 in salt-stable complexes independent of molybdate. The two minimum constructs that bound Hsp90 and Cdc37 contained the ␣-C-helix and the ␤4-and ␤5-strands of the NL through to end of the CL and the NL through to the ␣-E-helix and the amino acids that cap the helix. Cdc37 interacted with only the NL and minimally required the ␣-C-helix and ␤4-and ␤5-strands of this lobe of Lck. The results indicate that the high affinity binding activity of Hsp90 is triggered through its interaction with adjacent subdomain structures of kinase catalytic domains. Furthermore, the ␣-C-helix and part of its adjoining loop connection to the ␤4-strand appear to be the primary determinants recognized by Cdc37.

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Heat-shock protein 90, a chaperone for folding and regulation

Cited by 733 publications

References 117 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

The complementation of yeast with human or Plasmodium falciparum Hsp90 confers differential inhibitor sensitivities

Definition of Protein Kinase Sequence Motifs That Trigger High Affinity Binding of Hsp90 and Cdc37

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