Skip to main content
SpringerLink
Log in

Hsp90 Inhibitors in the Clinic

  • Chapter
Molecular Chaperones in Health and Disease

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 172))

Abstract

Specific inhibitors of Hsp90 have recently entered human clinical trials. At the time of writing, trials have been initiated only in metastatic cancer, although a rationale exists for using these agents in a variety of human diseases where protein (mis)folding is involved in the disease pathophysiology. Hsp90 inhibitors offer a unique anti-cancer opportunity because they provide simultaneous combinatorial blockade ofmultiple oncogenic pathways. The first compound in this class, 17-AAG, has completed phase I trials and phase II trials are in progress. The toxicity has been manageable and evidence of possible clinical activity has been seen in metastatic melanoma, prostate cancer andmultiplemyeloma. Other inhibitors with improved properties are approaching clinical trials. This chapter presents an update of the current clinical trials using Hsp90 inhibitors, focussing on the areas that will be increasingly relevant in the next 5 years.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • An WG, Schulte TW, Neckers LM (2000) The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. Cell Growth Differ. 11: 355–360

    PubMed  CAS  Google Scholar 

  • Armstrong BK, Kricker A (1994) Cutaneous melanoma. Cancer Surv. 19-20:219–240

    PubMed  CAS  Google Scholar 

  • Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868

    Article  PubMed  CAS  Google Scholar 

  • Bagatell R, Whitesell L (2004) Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther 3:1021–1030

    PubMed  CAS  Google Scholar 

  • Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33Suppl:238–244

    PubMed  CAS  Google Scholar 

  • Banerji U, Walton M, Raynaud F, Kelland LR, Judson I, Workman P (2001) Validation of pharmacodynamic endpoints for the Hsp90 molecular chaperone inhibitor 17-allylamino 17-demethoxygeldanamycin (17-AAG) in a human tumour xenograft model. Proc Am Asso Cancer Res 42:833

    Google Scholar 

  • Banerji U, O’Donnell A, Scurr M, Benson C, Stapleton S, Raynaud F, Clarke PA, Turner A, Workman P, Judson I (2003) A pharmacokinetically (PK) — pharmacodynamically (PD) guided phase I trial of the heat shock protein (Hsp90) inhibitor 17-Allylamino, 17-demethoxygeldanamycin (17AAG). Proc Am Soc Clin Oncol 22:199

    Google Scholar 

  • Banerji U, O’Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, Simmons L, Maloney A, Raynaud F, Campbell M, Walton M, Lakhani S, Kaye S, Workman P, Judson I (2005) A Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of 17-allylamino, 17-demethoxygeldanamycin (17-AAG) in patients with advanced malignancies. J Clin Oncol 23:4152–4161)

    Article  PubMed  CAS  Google Scholar 

  • Banerji U, Walton M, Raynaud F, Grimshaw R, Kelland LR, Valentini M, Judson I, Workman P (2005b) Pharmacokinetic-Pharmacodynamic relationships for the HSP90 molecular chaperone inhbitors 17-Allylamino, 17-demethoxygeldanamycin (17-AAG) in human ovarian cancer models. Clin Cancer Res (in press)

    Google Scholar 

  • Barral JM, Broadley SA, Schaffar G, Hartl FU (2004) Roles of molecular chaperones in protein misfolding diseases. Semin Cell Dev Biol 15:17–29

    Article  PubMed  CAS  Google Scholar 

  • Baselga J, Albanell J, Molina MA, Arribas J (2001) Mechanism of action of trastuzumab and scientific update. Semin Oncol 28:4–11

    Article  PubMed  CAS  Google Scholar 

  • Bearss DJ, Hurley LH, Von Hoff DD (2000) Telomere maintenance mechanisms as a target for drug development. Oncogene 19:6632–6641

    PubMed  CAS  Google Scholar 

  • Beliakoff J, Bagatell R, Paine-Murrieta G, Taylor CW, Lykkesfeldt AE, Whitesell L (2003) Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors. Clin Cancer Res 9: 4961–4971

    PubMed  CAS  Google Scholar 

  • Braga-Basaria M, Hardy E, Gottfried R, Burman KD, Saji M, Ringel MD (2004) 17-Allylamino-17-demethoxygeldanamycin activity against thyroid cancer cell lines correlateswith heat shock protein 90 levels. J Clin Endocrinol Metab 89:2982–2988

    Article  PubMed  CAS  Google Scholar 

  • Burger AM, Fiebig HH, Stinson SF, Sausville EA (2004) 17-(Allylamino)-17-demethoxygeldanamycin activity in human melanoma models. Anticancer Drugs 15:377–387

    PubMed  CAS  Google Scholar 

  • Chabner BA, Roberts TG (2005) Timeline: chemotherapy and the war on cancer. Nat Rev Cancer 5:65–72

    Article  PubMed  CAS  Google Scholar 

  • Chen LL, Trent JC, Wu EF, Fuller GN, Ramdas L, Zhang W, Raymond AK, Prieto VG, Oyedeji CO, Hunt KK, Pollock RE, Feig BW, Hayes KJ, Choi H, Macapinlac HA, Hittelman W, Velasco MA, Patel S, Burgess MA, Benjamin RS, Frazier ML (2004) A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 64:5913–5919

    PubMed  CAS  Google Scholar 

  • Cheung KM, Matthews T, James K, Aherne W, Rowlands M, Boxall K, Sharp S, Prodromou C, Pearl L, McDonald E, Workman P (2005) The identification, synthesis and in vitro biochemical evaluation of a new class of Hsp90 inhibitors. J Med Chem Bioorg Med Chem Lett 15:3338–3343

    CAS  Google Scholar 

  • Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ (2003) High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 348:1875–1883

    Article  PubMed  CAS  Google Scholar 

  • Chiosis G, Lucas B, Shtil A, Huezo H, Rosen N (2002) Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinase. Bioorg Med Chem 10:3555–3564

    PubMed  CAS  Google Scholar 

  • Chiosis G, Huezo H, Rosen N, Mimnaugh E, Whitesell L, Neckers L (2003) 1AAG: low target binding affinity and potent cell activity—finding an explanation. Mol Cancer Ther 2:123–129

    PubMed  CAS  Google Scholar 

  • Chiosis G, Vilenchik M, Kim J, Solit D (2004) Hsp90: the vulnerable chaperone. Drug Discov Today 9: 881–888

    Article  PubMed  CAS  Google Scholar 

  • Choo-Kang LR, Zeitlin PL (2001) Induction of Hsp70 promotes Delta F508 CFTR trafficking. Am J Physiol Lung Cell Mol Physiol 281:L58–L68

    PubMed  CAS  Google Scholar 

  • Chung J, Yoon S, Datta K, Bachelder RE, Mercurio AM (2004) Hypoxia-induced vascular endothelial growth factor transcription and protection from apoptosis are dependent on alpha6beta1 integrin in breast carcinoma cells. Cancer Res 64:4711–4716

    Article  PubMed  CAS  Google Scholar 

  • Chung YL, Troy H, Banerji U, Jackson LE, Walton M, Stubbs M, Griffiths JR, Judson I, Leach MO, Workman P, Ronen SM (2003) Magnetic resonance spectroscopic pharmacodynamic markers of the heat shock protien inhibitor 17-allyamino, 17-demethoxy-geldanamycin (17-AAG) in human colon cancer models. J Natl Cancer Inst 95: 1624–1633

    PubMed  CAS  Google Scholar 

  • Clarke PA, Hostein I, Banerji U, Stefano FD, Maloney A, Walton M, Judson I, Workman P (2000) Gene expression profiling of human colon cancer cells following inhibition of signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of the hsp90 molecular chaperone. Oncogene 19: 4125–4133

    PubMed  CAS  Google Scholar 

  • Cohen FE, Kelly JW (2003) Therapeutic approaches to protein-misfolding diseases. Nature 426:905–909

    PubMed  CAS  Google Scholar 

  • Daude N, Marella M, Chabry J (2003) Specific inhibition of pathological prion protein accumulation by small interfering RNAs. J Cell Sci 116:2775–2779

    Article  PubMed  CAS  Google Scholar 

  • daRocha Dias S, Light Y, Friedlos F, Springer C, Workman P, Marais R (2005) Oncogenic BRAF is an Hsp90 client protein that is targetted by the anti-cancer drug 17-AAG. Cancer Res (in press)

    Google Scholar 

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417: 949–954

    Article  PubMed  CAS  Google Scholar 

  • De Carcer G, do Carmo Avides M, Lallena MJ, Glover DM, Gonzalez C (2001) Requirement of Hsp90 for centrosomal function reflects its regulation of Polo kinase stability. EMBO J 20:2878–2884

    PubMed  Google Scholar 

  • DeVita VT Jr, Hellman S, Rosenberg SA (2001) Cancer: principles and practise of oncology, 6 edn. Lippincott, Williams and Wilkins, Philadelphia

    Google Scholar 

  • Druker BJ (2003) David A. Karnofsky Award lecture. Imatinib as a paradigm of targeted therapies. J Clin Oncol 21:239S–245S

    Article  PubMed  Google Scholar 

  • Dymock B, Drysdale M, McDonald E, Workman P (2004) Inhibitors of Hsp90 and other chaperones for the treatment of cancer. Expert Opin Ther Patents 14:837–847

    Article  CAS  Google Scholar 

  • Dymock BW, Barril X, Brough PA, Cansfield JE, Massey A, McDonald E, Hubbard RE, Surgenor A, Roughley SD, Webb P, Workman P, Wright L, Drysdale MJ (2005) Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J Med Chem 48:4212–4215

    Article  PubMed  CAS  Google Scholar 

  • Eder JP, Wheeler CA, Teicher BA, Schnipper LE (1991) A phase I clinical trial of novobiocin, a modulator of alkylating agent cytotoxicity. Cancer Res 51:510–513

    PubMed  CAS  Google Scholar 

  • Egorin MJ, Zuhowski EG, Rosen DM, Sentz DL, Covey JM, Eiseman JL (2001) Plasma pharmacokinetics and tissue distribution of 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507) in CDF1 mice. Cancer Chemother Pharmacol 47: 291–302

    Article  PubMed  CAS  Google Scholar 

  • Eigentler TK, Caroli UM, Radny P, Garbe C (2003) Palliative therapy of disseminated malignant melanoma: a systematic review of 41 randomised clinical trials. Lancet Oncol 4:748–759

    Article  PubMed  CAS  Google Scholar 

  • Eiseman JL, Lan J, Lagattuta TF, Hamburger DR, Joseph E, Covey JM, Egorin MJ (2005) Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl] amino]geldanamycin(1DMAG,NSC707545) in C.B-17 SCID mice bearingMDA-MB-231 human breast cancer xenografts. Cancer Chemother Pharmacol 55:21–32

    Article  PubMed  CAS  Google Scholar 

  • Ellis GK, Crowley J, Livingston RB, Goodwin JW, Hutchins L, Allen A (1991) Cisplatin and novobiocin in the treatment of non-small cell lung cancer. A Southwest Oncology Group study. Cancer 67:2969–2973

    CAS  Google Scholar 

  • Erlichman C, Toft D, Reid J, Sloan J, Atherton P, Adjei A, Ames M, Croghan G (2001) A phase I trial of 17 allylamino geldanamycin in patients with advanced cancer. Proc Am Asso Cancer Res 42:833

    Google Scholar 

  • Erlichman C, Toft D, Reid J, Goetz M, Ames M, Mandrekar A, Ajei A, McCollum A, Ivy P (2004) A Phase I trial of 17-allylamino-geldanamycin) (1AAG) in patients with advanced cancer (abstract). Proc Am Assoc Clin Oncol 23: 3030

    Google Scholar 

  • Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE (2001) Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem 276:15571–15574

    Article  PubMed  CAS  Google Scholar 

  • Fuller W, Cuthbert AW (2000) Post-translational disruption of the delta F508 cystic fibrosis transmembrane conductance regulator (CFTR)-molecular chaperone complex with geldanamycin stabilizes delta F508 CFTR in the rabbit reticulocyte lysate. J Biol Chem 275:37462–37468

    Article  PubMed  CAS  Google Scholar 

  • Gelmon KA, Eisenhauer EA, Harris AL, Ratain MJ, Workman P (1999) Anticancer agents targeting signaling molecules and cancer cell environment: challenges for drug development? J Natl Cancer Inst 91:1281–1287

    Article  PubMed  CAS  Google Scholar 

  • George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F, Sigua C, Sondarva G, Moscinski L, Atadja P, Bhalla K (2005) Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT. Blood 105:1768–1776

    PubMed  CAS  Google Scholar 

  • Goetz M, Toft D, Reid J, Sloan J, Atherton P, Adjei A, Croghan G, Weinshilboum R, Erlichman C, Ames M (2002) A phase I trial of 17-allyaminodemethoxygeldanamycin (17-AAG) in patients with advanced cancer. Proceedings EORTC-NCI-AACR Symposium of Molecular Cancer Therapeutics. Eur J Cancer 38[Suppl]:S54

    Google Scholar 

  • Goetz MP, Toft D, Reid J, Ames M, Stensgard B, Safgren S, Adjei AA, Sloan J, Atherton P, Vasile V, Salazaar S, Adjei A, Croghan G, Erlichman C (2005) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. J Clin Oncol 23:1078–1087

    PubMed  CAS  Google Scholar 

  • Gore L, Holden SN, Basche M, Raj SKS, Arnold I, O’Bryant C, Witta S, Rohde B, McCoy C, Eckhardt SG (2004) Updated results from a phase I trial of the histone deacetylase (HDAC) inhibitor MS-275 in patients with refractory solid tumours. Proc Am Soc Clin Oncol 22:3026

    Google Scholar 

  • Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, Sawyers CL (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293:876–880

    Article  PubMed  CAS  Google Scholar 

  • Gossett DR, Bradley MS, Jin X, Lin J (2005) 17-Allyamino-17-demethoxygeldanamycin and 17-NN-dimethyl ethylene diamine-geldanamycin have cytotoxic activity against multiple gynecologic cancer cell types. Gynecol Oncol 96: 381–388

    Article  PubMed  CAS  Google Scholar 

  • Grem JL, Morrison G, Guo XD, Agnew E, Takimoto CH, Thomas R, Szabo E, Grochow L, Grollman F, Hamilton JM, Neckers L, Wilson RH (2005) Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors. J Clin Oncol 23:1885–1893

    Article  PubMed  CAS  Google Scholar 

  • Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, Neckers LM, Toft DO (1997) The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem 272:23843–23850

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  • Hollingshead M, Alley M, Burger AM, Borgel S, Pacula-Cox C, Fiebig HH, Sausville EA (2005) In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol. Cancer Chemother Pharmacol 56:115–125

    CAS  Google Scholar 

  • Hostein I, Robertson D, DiStefano F, Workman P, Clarke PA (2001) Inhibtion of signal transduction by Hsp90 inhibitor 17-allylamino, 17-demethoxygeldanamycin results in cytostasis and apoptosis. Cancer Res 61: 4003–4009

    PubMed  CAS  Google Scholar 

  • Itoh H, Ogura M, Komatsuda A, Wakui H, Miura AB, Tashima Y (1999) A novel chaperoneactivity-reducing mechanism of the 90-kDa molecular chaperone Hsp90. Biochem J 343:697–703

    Article  PubMed  CAS  Google Scholar 

  • Jaattela M (1999) Escaping cell death: survival proteins in cancer. Exp Cell Res 248:30–43

    Article  PubMed  CAS  Google Scholar 

  • Jemal A, Thomas A, Murray T, Thun M (2002) Cancer statistics, 20CA. Cancer J Clin 52:23–47

    Article  Google Scholar 

  • Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410

    Article  PubMed  CAS  Google Scholar 

  • Kawano R, Ohshima K, Karube K, Yamaguchi T, Kohno S, Suzumiya J, Kikuchi M, Tamura K (2004) Prognostic significance of hepatocyte growth factor and c-MET expression in patients with diffuse large B-cell lymphoma. Br J Haematol 127:305–307

    Article  PubMed  CAS  Google Scholar 

  • Kelland LR, Sharp SY, Rogers PM, Myers TG, Workman P (1999) DT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90. J Natl Cancer Inst 91: 1940–1949

    Article  PubMed  CAS  Google Scholar 

  • Kiang JG, Bowman PD, Wu BW, Hampton N, Kiang AG, Zhao B, Juang YT, Atkins JL, Tsokos GC (2004) Geldanamycin treatment inhibits hemorrhage-induced increases in KLF6 and iNOS expression in unresuscitated mouse organs: role of inducible Hsp70. J Appl Physiol 97:564–569

    Article  PubMed  CAS  Google Scholar 

  • Kola I, Landis J (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3: 711–715

    Article  PubMed  CAS  Google Scholar 

  • Kristeleit RS, Tandy D, Atadja P, Patnaik A, Scott J, De Bono JS, Judson I, Kaye SB, Workman P, Aherne W (2004) Effects of the histone deacetylase inhibitor (HDACi) LAQ824 on histone acetylation, Hsp70 and c-Raf in peripheral blood lymphocytes from patients with advanced solid tumours enrolled in a phase I clinical trial. Proc Am Soc Clin Oncol 22:3032

    Google Scholar 

  • Kumar R, Musiyenko A, Barik S (2003) The heat shock protein 90 of Plasmodiumfalciparum and antimalarial activity of its inhibitor, geldanamycin. Malar J 2:30

    Article  PubMed  Google Scholar 

  • Latchman DS (2001) Heat shock proteins and cardiac protection. Cardiovasc Res 51:637–646

    Article  PubMed  CAS  Google Scholar 

  • Llauger L, He H, Kim J, Aguirre J, Rosen N, Peters U, Davies P, Chiosis G (2005) Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90. J Med Chem 48: 2892–2905

    Article  PubMed  CAS  Google Scholar 

  • Longley BJ Jr, Metcalfe DD, Tharp M, Wang X, Tyrrell L, Lu SZ, Heitjan D, Ma Y (1999) Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A 96:1609–1614

    Article  PubMed  CAS  Google Scholar 

  • Mallucci G, Dickinson A, Linehan J, Klohn PC, Brandner S, Collinge J (2003) Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302:871–874

    Article  PubMed  CAS  Google Scholar 

  • Maloney A, Workman P (2002) Hsp90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin Biol Ther 2:3–24

    Article  PubMed  CAS  Google Scholar 

  • Manola J, Atkins M, Ibrahim J, Kirkwood J (2000) Prognostic factors in metastaticmelanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18:3782–3793

    PubMed  CAS  Google Scholar 

  • Marcu M, Neckers L (2003) The C-Terminal half of heat shock protein 90 represents a second site for pharmacologic intervention in chaperone function. Curr Cancer Drug Targets 3:343–347

    Article  PubMed  CAS  Google Scholar 

  • Marcu MG, Chadli A, Bouhouche I, Catelli M, Neckers LM (2000) The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone. J Biol Chem 275:37181–37186

    Article  PubMed  CAS  Google Scholar 

  • Matthews RC, Burnie JP (2004) Recombinant antibodies: a natural partner in combinatorial antifungal therapy. Vaccine 22:865–871

    Article  PubMed  CAS  Google Scholar 

  • Matthews RC, Rigg G, Hodgetts S, Carter T, Chapman C, Gregory C, Illidge C, Burnie J (2003) Preclinical assessment of the efficacy of mycograb, a human recombinant antibody against fungal HspAntimicrob Agents Chemother 47: 2208–2216

    CAS  Google Scholar 

  • Minet E, Mottet D, Michel G, Roland I, Raes M, Remacle J, Michiels C (1999) Hypoxia-induced activation of HIF-1: role of HIF-1alpha-Hsp90 interaction. FEBS Lett 460:251–256

    Article  PubMed  CAS  Google Scholar 

  • Mitsiades C, Chanan-Khan A, Alsina M, Dass D, Landrigan D, Keitner M, Albitar GF, Hannah AL, Richardson P (2005) Phase I trial of 17-AAG in patients with relapsed and refractory multiple myeloma (MM). Proc American Assoc Clin Onc 23:3056

    Google Scholar 

  • Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC (2002) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374–14379

    Article  PubMed  CAS  Google Scholar 

  • Nardai G, Sass B, Eber J, Orosz G, Csermely P (2000) Reactive cysteines of the 90-kDa heat shock protein, Hsp90. Arch Biochem Biophys 384:59–67

    Article  PubMed  CAS  Google Scholar 

  • Neckers L, Ivy P (2003). Heat Shock Protein 90. Curr Opin Oncol 15:419–24

    PubMed  CAS  Google Scholar 

  • Nooney L, Matthews RC, Burnie JP (2005) Evaluation of mycograb, amphotericin B, caspofungin, and fluconazole in combination against Cryptococcus neoformans by checkerboard and time-kill methodologies. Diagn Microbiol Infect Dis. 51:19–29

    Article  PubMed  CAS  Google Scholar 

  • Nottage M, Siu LL (2002) Principles of clinical trial design. J Clin Oncol 20:42S–46S

    PubMed  Google Scholar 

  • Ochel HJ, Gademann G (2004) Destabilization of the non-pathogenic, cellular prion-protein by a small molecular drug. Antivir Ther 9:441–445

    PubMed  CAS  Google Scholar 

  • Okabe M, Uehara Y, Miyagishima T, Itaya T, Tanaka M, Kuni-Eda Y, Kurosawa M, Miyazaki T (1992) Effect of herbimycin A, an antagonist of tyrosine kinase, on bcr/abl oncoprotein-associated cell proliferations: abrogative effect on the transformation of murine hematopoietic cells by transfection of a retroviral vector expressing oncoprotein P210bcr/abl and preferential inhibition on Ph1-positive leukemia cell growth. Blood 80:1330–1338

    PubMed  CAS  Google Scholar 

  • Okada M, Itoh H, Hatakeyama T, Tokumitsu H, Kobayashi R (2003) Hsp90 is a direct target of the anti-allergic drugs disodium cromoglycate and amlexanox. Biochem J 374:433–441

    Article  PubMed  CAS  Google Scholar 

  • Orr HT (2004) Neurodegenerative disease: neuron protection agency. Nature 431:747–748

    Article  PubMed  CAS  Google Scholar 

  • Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520

    Article  PubMed  CAS  Google Scholar 

  • Prodromou C, Roe SM, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1997) Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90:65–75

    Article  PubMed  CAS  Google Scholar 

  • Ramanathan RK, Trump DL, Eiseman JL, Belani P, Agarwala S, Zuhowski EG, Lan J, Ivy P (2004) A phase I pharmacokinetic (PK) and pharmacodynamic (PD) trial of weekly 17-allylamino-17 demethoxygeldanamcyin (17-AAG, NSC-704057) in patients with advanced tumors (abstract). Proc Am Assoc Clin Oncol 23:3031

    Google Scholar 

  • Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617

    Article  PubMed  CAS  Google Scholar 

  • Rosenhagen MC, Soti C, Schmidt U, Wochnik GM, Hartl FU, Holsboer F, Young JC, Rein T (2003) The heat shock protein 90-targeting drug cisplatin selectively inhibits steroid receptor activation. Mol Endocrinol 17: 1991–2001

    Article  PubMed  CAS  Google Scholar 

  • Rowlands MG, Newbatt YM, Prodromou C, Pearl LH, Workman P, Aherne W (2004) High-throughput screening assay for inhibitors of heat-shock protein 90 ATPase activity. Anal Biochem 327:176–183

    Article  PubMed  CAS  Google Scholar 

  • Rutherford SL, Lindquist S (1998) Hsp90 as a capacitor formorphological evolution. Nature 396:336–342

    Article  PubMed  CAS  Google Scholar 

  • Santos NC, Figueria-Coelho J, Martin-Silva J (2003) Multidisciplinary utilization of dimethyl sulfoxide: pharmacological, cellular and molecular aspects. Biochem Pharmacol 65:1035–1041

    Article  PubMed  CAS  Google Scholar 

  • Sato S, Fujita N, Tsuruo T (2000) Modulation of Akt kinase activity by binding to HspProc Natl Acad Sci U S A 97:10832–10837

    CAS  Google Scholar 

  • Sausville EA, Tomaszewski JE, Ivy P (2003) Clinical development of 17-allylamino, 17-demethoxygeldanamycin. Curr Cancer Drug Targets 3:377–383

    Article  PubMed  CAS  Google Scholar 

  • Scherer FM (2004) The pharmaceutical industry-prices and progress. N Engl J Med 351:927–932

    Article  PubMed  CAS  Google Scholar 

  • Schnur RC, Corman ML, Gallaschun RJ, Cooper BA, Dee MF, Doty JL, Muzzi ML, DiOrio CI, Barbacci EG, Miller PE et al. (1995) erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships. J Med Chem 38:3813–3820

    PubMed  CAS  Google Scholar 

  • Schulte TW, Blagosklonny MV, Romanova L, Mushinski JF, Monia BP, Johnston JF, Nguyen P, Trepel J, Neckers LM (1996) Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway. Mol Cell Biol 16:5839–5845

    PubMed  CAS  Google Scholar 

  • Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CL (2002) Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2:117–125

    Article  PubMed  CAS  Google Scholar 

  • Sheriff M, Clarke PA, Workman P (2004) Factors that govern the cell death response induced by inhibition of the molecular chaperone heat shock protein 90. Eur J Cancer 2:97

    Google Scholar 

  • Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B (1999) Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341:1565–1571

    Article  PubMed  CAS  Google Scholar 

  • Sittler A, Lurz R, Lueder G, Priller J, Lehrach H, Hayer-Hartl MK, Hartl FU, Wanker EE (2001) Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Hum Mol Genet 10:1307–1315

    Article  PubMed  CAS  Google Scholar 

  • Slamon D, Pegram M (2001) Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. Semin Oncol 28:13–19

    Article  PubMed  CAS  Google Scholar 

  • Soga S, Shiotsu Y, Akinaga S, Sharma SV (2003) Development of radicicol analogues. Curr Cancer Drug Targets. 3:359–369

    Article  PubMed  CAS  Google Scholar 

  • Soldano KL, Jivan A, Nicchitta CV, Gewirth DT (2003) Stucture of the N-terminal domain of GRP94: basis for ligand specificity and regulation. J Biol Chem 48:48330–48338

    Google Scholar 

  • Solit DB, Zheng FF, Drobnjak M, Munster PN, Higgins B, Verbel D, Heller G, Tong W, Cordon-Cardo C, Agus DB, Scher HI, Rosen N (2002) 17-Allylamino-17-demethoxygeldanamycin induces the degradation of androgen receptor and HER-2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res 8:986–993

    PubMed  CAS  Google Scholar 

  • Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N (2003a) Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 63:2139–2144

    PubMed  CAS  Google Scholar 

  • Solit DB, Scher HI, Rosen N (2003b) Hsp90 as a therapeutic target in prostate cancer. Semin Oncol 30: 709–716

    Article  PubMed  CAS  Google Scholar 

  • Solit DB, Egorin M, Valetin G, Delacruz QYe, Schwartz L, Larson N, Rosen N, Scher HI (2004) A Phase 1 pharmacokinetic and pharmacodynamic trial of decetaxol and 1AAG (17-allylamin-17-demethoxygeldanamycin). Proc Am Assoc Clin Oncol 22:3032

    Google Scholar 

  • Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP (1997) Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89:239–250

    Article  PubMed  CAS  Google Scholar 

  • Sugita T, Tanaka S, Murakami T, Miyoshi H, Ohnuki T (1999) Immunosuppressive effects of the heat shock protein 90-binding antibiotic geldanamycin. Biochem Mol Biol Int 47:587–595

    PubMed  CAS  Google Scholar 

  • Supko JG, Hickman RL, Grever MR, Malspeis L (1995) Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 36:305–515

    PubMed  CAS  Google Scholar 

  • Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512

    Article  PubMed  CAS  Google Scholar 

  • Toms JR (2004) CancerStats Monograph. Cancer Research UK, London

    Google Scholar 

  • Tsan MF, Gao B (2004) Cytokine function of heat shock proteins. Am J Physiol Cell Physiol 286:C739–C744

    Article  PubMed  CAS  Google Scholar 

  • Van Oosterom AT, Judson IR, Verweij J, Stroobants S, Dumez H, Donato dP, Sciot R, van Glabbeke M, Dimitrijevic S, Nielsen OS (2002) Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: a report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 38[Suppl] 5:S83–S87

    PubMed  Google Scholar 

  • Wax S, Piecyk M, Maritim B, Anderson P (2003) Geldanamycin inhibits the production of inflammatory cytokines in activated macrophages by reducing the stability and translation of cytokine transcripts. Arthritis Rheum 48: 541–550

    Article  PubMed  CAS  Google Scholar 

  • Weber D (2003) Thalidomide and its derivatives: new promise for multiple myeloma. Cancer Control 10: 375–383

    PubMed  Google Scholar 

  • Weissmann C (2004) The state of the prion. Nat Rev Microbiol. 2:861–871

    Article  PubMed  CAS  Google Scholar 

  • Whitesell L, Sutphin PD, Pulcini EJ, Martinez JD, Cook PH (1998) The physical association of multiple molecular chaperone proteins with mutant p53 is altered by geldanamycin, an hsp90-binding agent. Mol Cell Biol 18: 1517–1524

    PubMed  CAS  Google Scholar 

  • Workman P (2005) Genomics and the second golden era of cancer drug development. Molecular BioSystems in press

    Google Scholar 

  • Workman P (2004) Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett 206:149–157

    Article  PubMed  CAS  Google Scholar 

  • Wright L, Barril X, Dymock B, Sheridan L, Surgenor A, Beswick M, Drysdale M, Collier A, Massey A, Davies N, Fink A, Fromont C, Aherne W, Boxall K, Sharp S, Workman P, Hubbard RE (2004) Structure-activity relationships in purine-based inhibitor binding to Hsp90 isoforms. Chem Biol 11:775–785

    Article  PubMed  CAS  Google Scholar 

  • Xu L, Eiseman JL, Egorin MJ, D’Argenio DZ (2003) Physiologically-based pharmacokinetics and molecular pharmacodynamics of 17-(allylamino)-17-demethoxygeldanamycin and its active metabolite in tumor-bearing mice. J Pharmacokinet Pharmacodyn 30:185–219

    Article  PubMed  CAS  Google Scholar 

  • Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L (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

    PubMed  CAS  Google Scholar 

  • Yu X, Guo ZS, Marcu MG, Neckers L, Nguyen DM, Chen GA, Schrump DS (2002) Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst 94:504–513

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Institute of Cancer Research, Haddow Laboratories, Cancer Research UK Centre for Cancer Therapeutics, Sutton, Surrey, SM2 5NG, UK

    S. Pacey, I. Judson & P. Workman

  2. The Royal Marsden Foundation NHS Trust, Downs Road, Sutton, Surrey, SM2 5PT, UK

    U. Banerj

Authors
  1. S. Pacey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. U. Banerj
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Judson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. Workman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Workman .

Editor information

Editors and Affiliations

  1. Freiburg i.

    K. Starke

  2. Medical School Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Matthias Gaestel (Professor) (Professor)

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Pacey, S., Banerj, U., Judson, I., Workman, P. (2006). Hsp90 Inhibitors in the Clinic. In: Starke, K., Gaestel, M. (eds) Molecular Chaperones in Health and Disease. Handbook of Experimental Pharmacology, vol 172. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-29717-0_14

Download citation

Publish with us

Policies and ethics

Search

Navigation