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. 2012 Jul;4(4):211–218. doi: 10.1177/1758834012445574

Heat shock protein 90 inhibition: rationale and clinical potential

Robert B Den 1, Bo Lu 2,✉
PMCID: PMC3384095  PMID: 22754594

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone protein essential for cellular survival. Functionally, HSPs promote proper protein folding, prevent misfolding, and restore three-dimensional protein structure which is critical following toxic cellular stresses. Recently, targeting HSP90 pharmacologically has gained traction in cancer therapy. Oncogenic cells depend on their ability to withstand endogenous (anoxia, nutrient deprivation, pH changes, and deranged signaling pathways) and exogenous (chemotherapy and radiation therapy) stressors for survival. Pharmacological inhibition of HSP90 destabilizes proteins and leads to degradation through the proteasome. This article will review the utility of HSP90 inhibition, as well as the current adoption in clinical trials and practice.

Keywords: clinical trial, heat shock protein 90, pharmacological inhibition

Introduction

Heat shock protein 90 (HSP90) is a molecular chaperone protein essential for cellular survival. While ubiquitously expressed in unstressed normal cells, the HSP90 complex assists in the folding and function of a variety of client proteins [Whitesell and Lindquist, 2005]. Discovered in 1962, transcription of heat shock proteins (HSPs) were noted to be induced by thermal and anoxic stress in contrast to most other cellular proteins [Ritossa, 1996]. Functionally, HSPs promote proper protein folding, prevent misfolding, and restore three-dimensional protein structure which is critical following toxic cellular stresses [Morimoto et al. 1997]. In addition, HSP functions in promoting intracellular protein transport and cellular regulation.

There are over 175 client proteins involved in a multitude of cellular processes (e.g. cell cycle control, proliferative/antiapoptotic signaling) and many are activated in malignancy [Richardson et al. 2011]. Client proteins include tyrosine kinases (e.g. Akt and MEK), transcription factors [i.e. androgen receptor (AR), estrogen receptor (ER), and p53], and structural proteins (tubulin, actin) [Goetz et al. 2003]. Multiple proteins involved in cell-specific oncogenic processes – BCR-ABL in chronic myelogenous leukemia [Peng and Li, 2007], NPM-ALK in lymphomas [Bonvini et al. 2002], mutated fms-like tyrosine kinase receptor-3 in acute myeloid leukemia (AML) [Knapper, 2007], and epidermal growth factor receptor (EGFR) kinase mutations in non-small cell lung cancer (NSCLC) [Shimamura et al. 2005] – are closely regulated by the binding of the HSP90 complex.

Recently, targeting HSP90 pharmacologically has gained traction in cancer therapy. Oncogenic cells depend on their ability to withstand endogenous (anoxia, nutrient deprivation, pH changes, and deranged signaling pathways) and exogenous (chemotherapy and radiation therapy) stressors for survival [Isaacs et al. 2003]. Pharmacological inhibition of HSP90 destabilizes proteins and leads to degradation through the proteasome [Sepp-Lorenzino et al. 1995]. Since HSP90 is involved in multiple redundant pathways critical for cell viability, its inhibition in multiple cancer animal models results in significant antitumor effects [Workman et al. 2007]. Further, this explains the potential benefit of HSP90 inhibition as sensitizers for traditional cytotoxics, which would otherwise have limited benefits [Neckers, 2007].

This article reviews the utility of HSP90 inhibition, as well as the current adoption in clinical trials and practice.

Heat shock protein 90 structure

HSP90 exists as a homodimer with an N-terminal domain that is critical for hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and is involved in interactions with chaperones [Richardson et al. 2011]. The HSP90 complex cycles from the ADP-bound state to the ATP-bound state and the conformational change that occurs with replacement of ADP by ATP stabilizes and activates client proteins. When ADP is rebound to HSP90, the client protein is released and may be marked for destruction by the proteasome through ubiquitination [Isaacs et al. 2003]. Thus HSP90 is able to protect client proteins in the presence of cellular stress (Figure 1).

Figure 1.

Figure 1.

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Heat shock protein 90 (HSP90) in vivo cycle. The client protein binds to the co-chaperones HSP70 and HSP40 and then is loaded onto the HSP90 homodimer. Subsequent binding of adenosine triphosphate (ATP) causes a conformational change that stabilizes the client proteins for interactions with other ligands or stimuli. If no further interaction occurs, hydrolysis of ATP to adenosine diphosphate (ADP) facilitates the release of the client protein, which can undergo degradation through the proteasome. The dissociation of ADP from the HSP90 homodimer restores HSP90 to its open conformation.

Heat shock protein 90 function in malignant cells

High-level expression of HSP90 and other chaperone proteins has been identified in multiple solid [Ciocca et al. 1993; Kaur and Ralhan, 1995] and hematologic tumors [Chant et al. 1995; Yufu et al. 1992] and are correlated with poor prognosis in breast cancer [Jameel et al. 1992]. Further, HSP90 expression facilitates tumor cell survival through inhibition of apoptosis and interactions of the chaperone complex with aberrant client proteins [Isaacs et al. 2003]. HSP90 stabilizes human epidermal growth factor receptor 2 (HER-2) in breast cancer and Bcr-Abl tyrosine kinase in chronic myeloid leukemia [Blagosklonny, 2001; Xu et al. 2001], key drivers in oncogenesis.

Heat shock protein 90 inhibition

Initial inhibitors of HSP90 included the naturally occurring products geldanamycin and radiciol [Whitesell et al. 1994]. While these molecules are structurally unrelated, both target the N-terminal domain nucleotide-binding site with higher affinity than either ATP or ADP. In addition, these inhibitors increase the recruitment of ubiquitin ligases to the HSP90 chaperone complex, leading to enhanced client protein degradation via the proteasome [Roe et al. 1999]. While the initial experiments demonstrated degradation of client proteins involved in oncogenic pathways [Mahalingam et al. 2009], their clinical use was not pursued due to poor in vivo activity as well as significant toxicity and difficulty in production.

Two geldanamycin analogues, 17 allylamino-17 demethoxygeldanamycin (17-AAG; tanespimycin) and 17 dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG; alvespimycin) improved upon the toxicity associated with geldanamycin and resulted in significantly improved chemical synthesis processes [Uehara, 2003]. In addition, it was demonstrated that 17-AAG bound cancer cells with more than 100-fold higher affinity than HSP90 in normal cells, implying that inhibitors had a tumor-specific affinity [Kamal et al. 2003]. However, this is debated within the literature and remains an area of active investigation.

17-AAG has been tested in more than 30 clinical trials since 1999 either as a single agent or in combination with other approved agents such as bortzemib, imatinib, docetaxel, rituximab, and trastuzumab [Kim et al. 2009]. Exciting data with trastuzumab demonstrated that the combination of 17-AAG and trastuzumab had activity in patients with HER-2-positive metastatic breast cancer who had previously progressed on trastuzumab monotherapy [Modi et al. 2007]. Pharmacological factors that hampered 17-AAG clinical use were difficulties with formulation and poor aqueous solubility of the compound. 17-DMAG was developed as a potent HSP90 inhibitor with improved pharmacokinetic properties. While 17-DMAG also demonstrated clinical activity as a single agent [Lancet et al. 2010] or when combined with chemotherapy, toxicity precluded further clinical testing [Glaze et al. 2005].

A reduced form of 17-AAG, retaspimycin (IPI-504) [Sydor et al. 2006], was shown to be a more potent HSP90 inhibitor compared with 17-AAG in biochemical binding assays. The increased solubility allows for simple aqueous-based intravenous formulations for clinical administration [Ge et al. 2006]. There are currently two open studies of IPI-504 for patients with non-small cell lung cancer (phase II in combination with docetaxel and a phase Ib/II in combination with everolimus; see http://www.cancertrials.gov).

A metabolite of 17-AAG [Egorin et al. 1998], the de-allylated analogue 17-amino-17 demethoxygeldanamycin (17-AG) has been formulated as an oral agent. It has been shown to act as a potent HSP90 inhibitor with in vivo activity against gastrointestinal stromal tumor (GIST) [Floris et al. 2011]. However, there are currently no open trials using this compound (Clinical Trials.gov) nor is it listed on the company’s website (http://www.infi.com).

There are several limitations to these natural compounds. First, toxicity, specifically hepatotoxicity, may be mediated through cellular depletion of glutathione[Cysyk et al. 2006]. Second, the relative importance of the cellular oxiodreductase NQO1 [NAD(P)H:quinone oxidoreductase 1] is currently under active observation. It is unclear whether NQO1 levels correlate with either cell sensitivity or growth inhibition to 17-AAG [Douglas et al. 2009; Guo et al. 2005]. One of the largest challenges for this drug class has been to identify a tolerable dose and schedule that provides therapeutic benefit. These limitations are currently being overcome with new synthetic HSP90 inhibitors.

Synthetic heat shock protein 90 inhibitors

Novel synthetic HSP90 inhibitors based on diverse chemical scaffolds have been developed with some in the preclinical space and others being used in clinical trials.

Based upon the 17-AAG backbone, a nonquinone phenol derivative has been shown to have antitumor activity in mouse xenograft models and a signature HSP90 inhibitor pharmacodynamic response [Menzella et al. 2009; Zhang et al. 2008]. These compounds are currently in preclinical development.

Synthetic analogues of radicicol have overcome the lack of in vivo activity of radiciol due to modifications of the multiple electrophilic sites that lead to metabolic deactivation of the compound [Yang et al. 2004]. The newest derivatives have demonstrated antitumor activity in animal models and are effective at doses below the maximum tolerated dose, implying a widening of the therapeutic window [Barluenga et al. 2008]. Currently four compounds STA-9090, NVP-AUY922, KW-2478, and AT-13387, are in phase I–II clinical development [Lin et al. 2008]. All drugs are administered in intravenous formulations. STA-9090 is the furthest in development of this class with trials in AML, NSCLC, and breast cancer ongoing.

Another synthetic approach has been to design HSP90 inhibitors that mimic the shape adopted by ATP when bound to HSP90. These purine scaffold inhibitors exhibit phenotypic effects similar to geldanamycin. The most advanced compound is BIIB021 being developed by Biogen Idec (Weston, MA, USA) and is currently in several phase I and II clinical trials in patients with GIST and metastatic breast cancer.

There are currently two related molecules (CUDC-305 and NVP-BEP800) currently in preclinical testing. Both compounds have high oral bioavailability and CUDC-305 has shown high intracranial dose distribution [Bao et al. 2009; Brough et al. 2009]. A third orally available compound, SNX-5422, was recently acquired by Pfizer (New York, NY) with plans for phase I trials. SNX-5422 was found to be superior to 17-AAG in treatment of mutant EGFR NSCLC and has resulted in partial tumor regressions in in vivo testing [Chandarlapaty et al. 2008]. However, the development of SNX-5422 was recently discontinued due to reports of ocular toxicity and the potential for irreversible retinal damage [Rajan et al. 2011].

Finally there are several inhibitors whose structural classes are not disclosed. Early clinical trials are using MPC-3100, XL888, and Hsp990.

Heat shock protein 90 inhibition monitoring

Clinical assays to measure HSP90 inhibition generally focus on either measuring the levels of a number of HSP90 client proteins or induction of HSP70 from peripheral blood mononuclear cells (PBMCs) both pre- and postinhibitor administration of the HSP90 inhibitor. These pharmacodynamic studies have a reproducible index of in vivo activity, but lack tumor specificity [Grem et al. 2005; Kummar et al. 2010; Ramanathan et al. 2010].

Tumor biopsies to measure pharmacodynamic response have also been studied [Banerji et al. 2005], but this is challenging due to logistical and ethical issues with repeated invasive procedures. A noninvasive approach measuring levels of tumor HER-2 and vascular endothelial growth factor are being studied. Using novel positron emission tomography markers, gallium-68 or zirconium-89 labeled antibodies, tumor receptor expression is able to be monitored in real time. This strategy is currently being incorporated in clinical trials [Holland et al. 2010; Nagengast et al. 2010; Smith-Jones et al. 2006].

Conclusions/future

Currently, there are over 20 interventional trials listed on ClinicalTrials.gov utilizing HSP90 inhibitors (Table 1). This strong interest in HSP90 inhibition in the cancer armamentarium is encouraging, however several fundamental questions remain. First, which tumor type is best suited for study? While, HER-2 is the most sensitive client protein to HSP90 inhibition, multiple tumor types have shown in vivo preclinical activity. One approach is to target malignancies whose critical driver protein is a HSP90 client. This would apply to c-KIT in GIST, mutant EGFR in NSCLC, HER-2 in breast cancer, and so on.

Table 1.

Interventional trials listed on www.ClinicalTrials.gov utilizing heat shock protein 90 (HSP90) inhibitors.

HSP 90 inhibitor Route Clinical development stage Current status
17-AAG Intravenous Phase III Not in development
17-DMAG Intravenous Phase I Multiple phase I completed. One open trial: NCT01126502
ABI-010 Intravenous Phase I No active trials
IPI-504 Intravenous Phase II/III Two current open studies: NCT01362400, NCT01427946
AUY922 Intravenous Phase I–II Multiple phase II trials: NSCLC (NCT01124864), breast cancer (NCT00526045), pancreatic (NCT01484860), lymphoma (NCT01485536), GIST (NCT01404650, NCT01389583). Multiple ongoing combination studies: lapatinib (NCT01361945). bortezomib (NCT00708292), trastuzumab (NCT01271920; NCT01402401), erlotinib (NCT01259089), cetuximab (NCT01294826), capecitabine (NCT01226732)
STA-9090 Intravenous Phase I–III Multiple ongoing phase II trials in castrate-resistant prostate cancer (NCT01270880, NCT01368003), breast cancer (NCT01273896), colorectal cancer (NCT01111838), hematologic malignancies (NCT00858572, NCT00964873), esophagogastric cancer (NCT01167114), pancreatic cancer (NCT01227018), melanoma (NCT01200238), SCLC (NCT01173523), NSCLC (NCT01031225), GIST (NCT01039519), multiple (NCT01183364, NCT00687934, NCT00688116). One phase III trial in NSCLC (NCT01348126)
BIIB028 Intravenous Phase I One phase I complete (NCT00725933). No current open trials
KW-2478 Intravenous Phase I Phase I in multiple myeloma, CLL, NHL completed (NCT00457782). Phase I/II trial in combination with bortezomib for myeloma ongoing (NCT01063907)
AT13387 Intravenous Phase I Several ongoing phase I trials in solid tumors (NCT00878423, NCT01245218, NCT01246102). Ongoing randomized phase II trial +/− imatinib in GIST (NCT01294202)
PU-H71 Intravenous Phase I Single agent, advanced solid tumors/lymphoma (NCT01393509)
BIIB021 Oral Phase II Multiple phase I trials in solid tumors, breast, GIST, and CLL completed (NCT01017198, NCT01004081, NCT00618735, NCT00618319, NCT00412412, NCT00345189). One trial terminated by company (NCT00344786)
IPI-493 Oral Phase I Development halted
SNX-5422 Oral Phase I Development halted due to excessive ocular toxicity
XL888 Oral Phase I Phase I terminated. No active trials listed in ClinicalTrials.gov
HSP990 Oral Phase I Phase I studies ongoing in advanced solid tumors (NCT01064089; NCT00879905)
MPC-3100 Oral Phase I Phase I completed (NCT00920205). No current active trials
DS-2248 Oral Phase I Single agent, solid tumors (NCT01288430)
Debio 0932 Oral Phase I Single agent, advanced solid tumors/lymphoma (NCT01168752)
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17-AAG, 17 allylamino-17demethoxygeldanamycin; 17-DMAG, 17 dimethylaminoethylamino-17-demethoxygeldanamycin; CLL, chronic lymphocytic leukemia; GIST, gastrointestinal stromal tumor; IPI-504, retaspimycin; NHL, non-Hodgkin lymphoma; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

An alternative is to target HSP90 co-chaperones including HSP40, HSP70 or CDC37 [Trepel et al. 2010]. Zhang and colleagues demonstrated that celastrol inhibits the HSP90-CDC37 complex formation [Zhang et al. 2009]. This HSP90 co-chaperone complex is critical for regulating various kinases, including ERBB2, EGFR, and BRAF that are critical drivers in tumor formation and proliferation. Further, by specifically targeting these complexes, there might be less severe toxicities observed clinically.

Another approach is to use HSP90 inhibition as an adjuvant to other chemotherapeutics and shut down the heat shock response to increase cellular stress and protein degradation. However, one challenge is that the current drug development paradigm of identifying a maximum tolerated dose may not be applicable in this situation as target modulation is critical to the antitumor effects elicited with HSP90 inhibition. One major strength of HSP90 inhibitors is the therapeutic window created as HSP90 inhibitors selectively accumulate in tumor tissue over normal tissue. This rapid clearance from normal tissues and the blood compartment may inhibit traditional pharmacokinetic monitoring, dosing, and scheduling. Thus, direct tumor monitoring either by biopsy or noninvasive methods is critical to optimal clinical efficacy. Given, the recent developments of novel synthetic analogues with improved chemical properties, the future is quite promising for this class of agents.

Footnotes

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The author declares no conflicts of interest in preparing this article.

Contributor Information

Robert B. Den, Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA

Bo Lu, Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, 111 South 11th Street, Bodine Cancer Center, Philadelphia, PA 19107, USA.

References

  1. Banerji U., O’Donnell A., Scurr M., Pacey S., Stapleton S., Asad Y., et al. (2005) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23: 4152–4161 [DOI] [PubMed] [Google Scholar]
  2. Bao R., Lai C.J., Qu H., Wang D., Yin L., Zifcak B., et al. (2009) CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res 15: 4046–4057 [DOI] [PubMed] [Google Scholar]
  3. Barluenga S., Wang C., Fontaine J.G., Aouadi K., Beebe K., Tsutsumi S., et al. (2008) Divergent synthesis of a pochonin library targeting HSP90 and in vivo efficacy of an identified inhibitor. Angew Chem Int Ed Engl 47: 4432–4435 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Blagosklonny M.V. (2001) Re: Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst 93: 239–240 [DOI] [PubMed] [Google Scholar]
  5. Bonvini P., Gastaldi T., Falini B., Rosolen A. (2002) Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Cancer Res 62: 1559–1566 [PubMed] [Google Scholar]
  6. Brough P.A., Barril X., Borgognoni J., Chene P., Davies N.G., Davis B., et al. (2009) Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone. J Med Chem 52: 4794–4809 [DOI] [PubMed] [Google Scholar]
  7. Chandarlapaty S., Sawai A., Ye Q., Scott A., Silinski M., Huang K., et al. (2008) SNX2112, a synthetic heat shock protein 90 inhibitor, has potent antitumor activity against HER kinase-dependent cancers. Clin Cancer Res 14: 240–248 [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chant I.D., Rose P.E., Morris A.G. (1995) Analysis of heat-shock protein expression in myeloid leukaemia cells by flow cytometry. Br J Haematol 90: 163–168 [DOI] [PubMed] [Google Scholar]
  9. Ciocca D.R., Clark G.M., Tandon A.K., Fuqua S.A., Welch W.J., McGuire W.L. (1993) Heat shock protein hsp70 in patients with axillary lymph node-negative breast cancer: prognostic implications. J Natl Cancer Inst 85: 570–574 [DOI] [PubMed] [Google Scholar]
  10. Cysyk R.L., Parker R.J., Barchi J.J., Jr, Steeg P.S., Hartman N.R., Strong J.M. (2006) Reaction of geldanamycin and C17-substituted analogues with glutathione: product identifications and pharmacological implications. Chem Res Toxicol 19: 376–381 [DOI] [PubMed] [Google Scholar]
  11. Douglas M., Lim A.R., Porter J.R., West K., Pink M.M., Ge J., et al. (2009) The antiproliferative activity of the heat shock protein 90 inhibitor IPI-504 is not dependent on NAD(P)H:quinone oxidoreductase 1 activity in vivo. Mol Cancer Ther 8: 3369–3378 [DOI] [PubMed] [Google Scholar]
  12. Egorin M.J., Rosen D.M., Wolff J.H., Callery P.S., Musser S.M., Eiseman J.L. (1998) Metabolism of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) by murine and human hepatic preparations. Cancer Res 58: 2385–2396 [PubMed] [Google Scholar]
  13. Floris G., Sciot R., Wozniak A., Van Looy T., Wellens J., Faa G., et al. (2011) The novel HSP90 inhibitor, IPI-493, is highly effective in human gastrointestinal stromal tumor xenografts carrying heterogeneous KIT mutations. Clin Cancer Res 17: 5604–5614 [DOI] [PubMed] [Google Scholar]
  14. Ge J., Normant E., Porter J.R., Ali J.A., Dembski M.S., Gao Y., et al. (2006) Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 49: 4606–4615 [DOI] [PubMed] [Google Scholar]
  15. Glaze E.R., Lambert A.L., Smith A.C., Page J.G., Johnson W.D., McCormick D.L., et al. (2005) Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance; Cancer Chemother Pharmacol 56: 637–647 [DOI] [PubMed] [Google Scholar]
  16. Goetz M.P., Toft D.O., Ames M.M., Erlichman C. (2003) The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol 14: 1169–1176 [DOI] [PubMed] [Google Scholar]
  17. Grem J.L., Morrison G., Guo X.D., Agnew E., Takimoto C.H., Thomas R., et al. (2005) Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 23: 1885–1893 [DOI] [PubMed] [Google Scholar]
  18. Guo W., Reigan P., Siegel D., Zirrolli J., Gustafson D., Ross D. (2005) Formation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibition. Cancer Res 65: 10006–10015 [DOI] [PubMed] [Google Scholar]
  19. Holland J.P., Caldas-Lopes E., Divilov V., Longo V.A., Taldone T., Zatorska D., et al. (2010) Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using Zr-DFO-trastuzumab. PLoS One 5: e8859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Isaacs J.S., Xu W., Neckers L. (2003) Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3: 213–217 [DOI] [PubMed] [Google Scholar]
  21. Jameel A., Skilton R.A., Campbell T.A., Chander S.K., Coombes R.C., Luqmani Y.A. (1992) Clinical and biological significance of HSP89 alpha in human breast cancer. Int J Cancer 50: 409–415 [DOI] [PubMed] [Google Scholar]
  22. Kamal A., Thao L., Sensintaffar J., Zhang L., Boehm M.F., Fritz L.C., et al. (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425: 407–410 [DOI] [PubMed] [Google Scholar]
  23. Kaur J., Ralhan R. (1995) Differential expression of 70-kDa heat shock-protein in human oral tumorigenesis. Int J Cancer 63: 774–779 [DOI] [PubMed] [Google Scholar]
  24. Kim Y.S., Alarcon S.V., Lee S., Lee M.J., Giaccone G., Neckers L., et al. (2009) Update on Hsp90 inhibitors in clinical trial. Curr Top Med Chem 9: 1479–1492 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Knapper S. (2007) FLT3 inhibition in acute myeloid leukaemia. Br J Haematol 138: 687–699 [DOI] [PubMed] [Google Scholar]
  26. Kummar S., Gutierrez M.E., Gardner E.R., Chen X., Figg W.D., Zajac-Kaye M., et al. (2010) Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur J Cancer 46: 340–347 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lancet J.E., Gojo I., Burton M., Quinn M., Tighe S.M., Kersey K., et al. (2010) Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia 24: 699–705 [DOI] [PubMed] [Google Scholar]
  28. Lin T.Y., Bear M., Du Z., Foley K.P., Ying W., Barsoum J., et al. (2008) The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors. Exp Hematol 36: 1266–1277 [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mahalingam D., Swords R., Carew J.S., Nawrocki S.T., Bhalla K., Giles F.J. (2009) Targeting HSP90 for cancer therapy. Br J Cancer 100: 1523–1529 [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Menzella H.G., Tran T.T., Carney J.R., Lau-Wee J., Galazzo J., Reeves C.D., et al. (2009) Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus. J Med Chem 52: 1518–1521 [DOI] [PubMed] [Google Scholar]
  31. Modi S., Stopeck A.T., Gordon M.S., Mendelson D., Solit D.B., Bagatell R., et al. (2007) Combination of trastuzumab and tanespimycin (17-AAG, KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer:a phase I dose-escalation study. J Clin Oncol 25: 5410–5417 [DOI] [PubMed] [Google Scholar]
  32. Morimoto R.I., Kline M.P., Bimston D.N., Cotto J.J. (1997) The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones. Essays Biochem 32: 17–29 [PubMed] [Google Scholar]
  33. Nagengast W.B., de Korte M.A., Oude Munnink T.H., Timmer-Bosscha H., den Dunnen W.F., Hollema H., et al. (2010) 89Zr-bevacizumab PET of early antiangiogenic tumor response to treatment with HSP90 inhibitor NVP-AUY922. J Nucl Med 51: 761–767 [DOI] [PubMed] [Google Scholar]
  34. Neckers L. (2007) Heat shock protein 90: the cancer chaperone. J Biosci 32: 517–530 [DOI] [PubMed] [Google Scholar]
  35. Peng C., Li D., Li S. (2007) Heat shock protein 90: a potential therapeutic target in leukemic progenitor and stem cells harboring mutant BCR-ABL resistant to kinase inhibitors. Cell Cycle 6: 2227–2231 [DOI] [PubMed] [Google Scholar]
  36. Rajan A., Kelly R.J., Trepel J.B., Kim Y.S., Alarcon S.V., Kummar S., et al. (2011) A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin Cancer Res 17: 6831–6839 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Ramanathan R.K., Egorin M.J., Erlichman C., Remick S.C., Ramalingam S.S., Naret C., et al. (2010) Phase I pharmacokinetic and pharmacodynamic study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors. J Clin Oncol 28: 1520–1526 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Richardson P.G., Mitsiades C.S., Laubach J.P., Lonial S., Chanan-Khan A.A., Anderson K.C. (2011) Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers. Br J Haematol 152: 367–379 [DOI] [PubMed] [Google Scholar]
  39. Ritossa F. (1996) Discovery of the heat shock response. Cell Stress Chaperones 1: 97–98 [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Roe S.M., Prodromou C., O’Brien R., Ladbury J.E., Piper P.W., Pearl L.H. (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem 42: 260–266 [DOI] [PubMed] [Google Scholar]
  41. Sepp-Lorenzino L., Ma Z., Lebwohl D.E., Vinitsky A., Rosen N. (1995) Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases. J Biol Chem 270: 16580–16587 [DOI] [PubMed] [Google Scholar]
  42. Shimamura T., Lowell A.M., Engelman J.A., Shapiro G.I. (2005) Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins. Cancer Res 65: 6401–6408 [DOI] [PubMed] [Google Scholar]
  43. Smith-Jones P.M., Solit D., Afroze F., Rosen N., Larson S.M. (2006) Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET. J Nucl Med 47: 793–796 [PMC free article] [PubMed] [Google Scholar]
  44. Sydor J.R., Normant E., Pien C.S., Porter J.R., Ge J., Grenier L., et al. (2006) Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti- cancer agent directed against Hsp90. Proc Natl Acad Sci U S A 103: 17408–17413 [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Trepel J., Mollapour M., Giaccone G., Neckers L. (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10: 537–549 [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Uehara Y. (2003) Natural product origins of Hsp90 inhibitors. Curr Cancer Drug Targets 3: 325–330 [DOI] [PubMed] [Google Scholar]
  47. Whitesell L., Lindquist S.L. (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5: 761–772 [DOI] [PubMed] [Google Scholar]
  48. Whitesell L., Mimnaugh E.G., De Costa B., Myers C.E., Neckers L.M. (1994) Inhibition of heat shock protein HSP90-pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci U S A 91: 8324–8328 [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Workman P., Burrows F., Neckers L., Rosen N. (2007) Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci 1113: 202–216 [DOI] [PubMed] [Google Scholar]
  50. Xu W., Mimnaugh E., Rosser M.F., Nicchitta C., Marcu M., Yarden Y., et al. (2001) Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem 276: 3702–3708 [DOI] [PubMed] [Google Scholar]
  51. Yang Z.Q., Geng X., Solit D., Pratilas C.A., Rosen N., Danishefsky S.J. (2004) New efficient synthesis of resorcinylic macrolides via ynolides: establishment of cycloproparadicicol as synthetically feasible preclinical anticancer agent based on Hsp90 as the target. J Am Chem Soc 126: 7881–7889 [DOI] [PubMed] [Google Scholar]
  52. Yufu Y., Nishimura J., Nawata H. (1992) High constitutive expression of heat shock protein 90 alpha in human acute leukemia cells. Leuk Res 16: 597–605 [DOI] [PubMed] [Google Scholar]
  53. Zhang M.Q., Gaisser S., Nur E.A.M., Sheehan L.S., Vousden W.A., Gaitatzis N., et al. (2008) Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors. J Med Chem 51: 5494–5497 [DOI] [PubMed] [Google Scholar]
  54. Zhang T., Li Y., Yu Y., Zou P., Jiang Y., Sun D. (2009) Characterization of celastrol to inhibit hsp90 and cdc37 interaction. J Biol Chem 284: 35381–35389 [DOI] [PMC free article] [PubMed] [Google Scholar]

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