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The Molecular Chaperones Interaction Networks in Protein Folding and Degradation pp 151–183Cite as

Designing Drugs Against Hsp90 for Cancer Therapy

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Part of the book series: Interactomics and Systems Biology ((INTERACTOM,volume 1))

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone exploited by cancer cells to aid the function of numerous oncoproteins. The recognition of Hsp90 as a critical facilitator for oncogene addiction and survival of the cancer cell has opened a promising new niche for cancer treatment. The serendipitous discovery that the broad spectrum anticancer activity of the natural products geldanamycin (GM) and radicicol (RD) was a result of inhibition of Hsp90 resulted in the development of improved derivatives of these natural products. One of these was 17 allylaminogeldanamycin (17-AAG), a closely related analog of GM, and was in fact the first Hsp90 inhibitor to enter the clinic. However, GM and its analogs suffer from poor “drug-like” properties and this served as a strong impetus for the development of novel synthetic Hsp90 inhibitors. These efforts resulted in the development of numerous potent synthetic small molecule inhibitors with significant scaffold diversity as well as superior pharmacokinetic and toxicity profile to have entered clinical trials. This review highlights the drug discovery efforts pertaining to the development of the first and second-generation Hsp90 inhibitors, and also gleans over their individual promise as clinical agents for anticancer therapy.

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References

  1. Ritossa F (1962) A new puffing pattern induced by temperature shock and DNP in drosophila. Cell Mol Life Sci 18(12):571–573

    CAS  Google Scholar 

  2. Tissieres A, Mitchell HK, Tracy UM (1974) Protein synthesis in salivary glands of Drosophila melanogaster: relation to chromosome puffs. J Mol Biol 84(3):389–398

    CAS  PubMed  Google Scholar 

  3. Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5(10):761–772. doi:10.1038/nrc1716

    CAS  PubMed  Google Scholar 

  4. Wegele H, Muller L, Buchner J (2004) Hsp70 and Hsp90–a relay team for protein folding. Rev Physiol Biochem Pharmacol 151:1–44. doi:10.1007/s10254-003-0021-1

    CAS  PubMed  Google Scholar 

  5. Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–294. doi:10.1146/annurev.biochem.75.103004.142738

    CAS  PubMed  Google Scholar 

  6. Wandinger SK, Richter K, Buchner J (2008) The Hsp90 chaperone machinery. J Biol Chem 283(27):18473–18477. doi:10.1074/jbc.R800007200

    CAS  PubMed  Google Scholar 

  7. Zuehlke A, Johnson JL (2010) Hsp90 and co-chaperones twist the functions of diverse client proteins. Biopolymers 93 (3):211–217. doi:10.1002/bip.21292

    CAS  PubMed Central  PubMed  Google Scholar 

  8. 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: 10.1196/annals.1391.012

    CAS  PubMed  Google Scholar 

  9. Neckers L (2002) Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 8(4 Suppl):S55–S61

    CAS  PubMed  Google Scholar 

  10. Trepel J, Mollapour M, Giaccone G, Neckers L (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10(8):537–549. doi:10.1038/nrc2887

    CAS  PubMed  Google Scholar 

  11. Porter JR, Fritz CC, Depew KM (2010) Discovery and development of Hsp90 inhibitors: a promising pathway for cancer therapy. Curr Opin Chem Biol 14(3):412–420. doi:10.1016/j.cbpa.2010.03.019

    CAS  PubMed  Google Scholar 

  12. Patel HJ, Modi S, Chiosis G, Taldone T (2011) Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment. Expert Opin Drug Discov 6(5):559–587. doi:10.1517/17460441.2011.563296

    CAS  PubMed Central  PubMed  Google Scholar 

  13. DeBoer C, Meulman PA, Wnuk RJ, Peterson DH (1970) Geldanamycin, a new antibiotic. J Antibiot (Tokyo) 23(9):442–447

    CAS  Google Scholar 

  14. Uehara Y, Hori M, Takeuchi T, Umezawa H (1986) Phenotypic change from transformed to normal induced by benzoquinonoid ansamycins accompanies inactivation of p60src in rat kidney cells infected with Rous sarcoma virus. Mol Cell Biol 6(6):2198–2206

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM (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(18):8324–8328

    CAS  PubMed Central  PubMed  Google Scholar 

  16. 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(1):65–75

    CAS  PubMed  Google Scholar 

  17. 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(2):239–250. doi:S0092-8674(00)80203-2

    CAS  PubMed  Google Scholar 

  18. 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(38):23843–23850

    CAS  PubMed  Google Scholar 

  19. Pratt WB (1998) The hsp90-based chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors. Proc Soc Exp Biol Med 217(4):420–434

    CAS  PubMed  Google Scholar 

  20. Roe SM, Prodromou C, O’Brien R, Ladbury JE, Piper PW, Pearl LH (1999) Structural basis for inhibition of the Hsp90 molecular chaperone by the antitumor antibiotics radicicol and geldanamycin. J Med Chem 42(2):260–266. doi:10.1021/jm980403y

    CAS  PubMed  Google Scholar 

  21. 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(6956):407–410. doi:10.1038/nature01913

    CAS  PubMed  Google Scholar 

  22. Moulick K, Ahn JH, Zong H, Rodina A, Cerchietti L, Gomes DGEM, Caldas-Lopes E, Beebe K, Perna F, Hatzi K, Vu LP, Zhao X, Zatorska D, Taldone T, Smith-Jones P, Alpaugh M, Gross SS, Pillarsetty N, Ku T, Lewis JS, Larson SM, Levine R, Erdjument-Bromage H, Guzman ML, Nimer SD, Melnick A, Neckers L, Chiosis G (2011) Affinity-based proteomics reveal cancer-specific networks coordinated by Hsp90. Nat Chem Biol 7(11):818–826. doi:10.1038/nchembio.670

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Jhaveri K, Taldone T, Modi S, Chiosis G (2012) Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 1823(3):742–755. doi:10.1016/j.bbamcr.2011.10.008

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Kamal A, Burrows FJ (2004) Hsp90 inhibitors as selective anticancer drugs. Discov Med 4(23):277–280

    PubMed  Google Scholar 

  25. Ardini E, Galvani A (2012) ALK inhibitors: a pharmaceutical perspective. Front Oncol 2:17. doi:10.3389/fonc.2012.00017

    PubMed Central  PubMed  Google Scholar 

  26. Kim YS, Alarcon SV, Lee S, Lee MJ, Giaccone G, Neckers L, Trepel JB (2009) Update on Hsp90 inhibitors in clinical trial. Curr Top Med Chem 9(15):1479–1492. doi:CTMC-Abs-031-9-15

    CAS  PubMed  Google Scholar 

  27. Donnelly A, Blagg BS (2008) Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr Med Chem 15(26):2702–2717

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Brandt GE, Blagg BS (2009) Alternate strategies of Hsp90 modulation for the treatment of cancer and other diseases. Curr Topics Med Chem 9(15):1447–1461

    CAS  Google Scholar 

  29. Gao Z, Garcia-Echeverria C, Jensen MR (2010) Hsp90 inhibitors: clinical development and future opportunities in oncology therapy. Curr Opin Drug Discov Dev 13(2):193–202

    CAS  Google Scholar 

  30. Janin YL (2010) ATPase inhibitors of heat-shock protein 90, second season. Drug Discov Today 15(9-10):342–353. doi:10.1016/j.drudis.2010.03.002

    CAS  PubMed  Google Scholar 

  31. Beebe K, Mollapour M, Scroggins B, Prodromou C, Xu W, Tokita M, Taldone T, Pullen L, Zierer BK, Lee MJ, Trepel J, Buchner J, Bolon D, Chiosis G, Neckers L (2013) Posttranslational modification and conformational state of Heat Shock Protein 90 differentially affect binding of chemically diverse small molecule inhibitors. Oncotarget 4(7):1065–1074

    PubMed Central  PubMed  Google Scholar 

  32. Anderson AC (2003) The process of structure-based drug design. Chem Biol 10(9):787–797. doi:10.1016/j.chembiol.20 03.09.002

    CAS  PubMed  Google Scholar 

  33. Erlanson DA, McDowell RS, O’Brien T (2004) Fragment-based drug discovery. J Med Chem 47(14):3463–3482. doi:10.1021/jm040031v

    CAS  PubMed  Google Scholar 

  34. Vilenchik M, Solit D, Basso A, Huezo H, Lucas B, He H, Rosen N, Spampinato C, Modrich P, Chiosis G (2004) Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90. Chem Biol 11(6):787–797. doi:10.1016/j.chembiol.2004.04.008

    CAS  PubMed  Google Scholar 

  35. Supko JG, Hickman RL, Grever MR, Malspeis L (1995) Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol 36(4):305–315

    CAS  PubMed  Google Scholar 

  36. Neckers L (2006) Chaperoning oncogenes: Hsp90 as a target of geldanamycin. Handb Exp Pharmacol 172:259–277

    CAS  PubMed  Google Scholar 

  37. Samuni A, Goldstein S (2012) Redox properties and thiol reactivity of geldanamycin and its analogues in aqueous solutions. J Phys Chem B 116(22):6404–6410. doi:10.1021/jp304206n

    CAS  PubMed  Google Scholar 

  38. Samuni Y, Ishii H, Hyodo F, Samuni U, Krishna MC, Goldstein S, Mitchell JB (2010) Reactive oxygen species mediate hepatotoxicity induced by the Hsp90 inhibitor geldanamycin and its analogs. Free Radic Biol Med 48(11):1559–1563. doi:10.1016/j.freeradbiomed.2010.03.001

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Tian ZQ, Liu Y, Zhang D, Wang Z, Dong SD, Carreras CW, Zhou Y, Rastelli G, Santi DV, Myles DC (2004) Synthesis and biological activities of novel 17-aminogeldanamycin derivatives. Bioorg Med Chem 12(20):5317–5329. doi:10.1016/j.bmc.2004.07.053

    CAS  PubMed  Google Scholar 

  40. Schulte TW, Neckers LM (1998) The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 42(4):273–279

    CAS  PubMed  Google Scholar 

  41. 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) Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23(18):4152–4161. doi:10.1200/JCO.2005.00.612

    CAS  PubMed  Google Scholar 

  42. 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(22):1940–1949

    CAS  PubMed  Google Scholar 

  43. Solit DB, Ivy SP, Kopil C, Sikorski R, Morris MJ, Slovin SF, Kelly WK, DeLaCruz A, Curley T, Heller G, Larson S, Schwartz L, Egorin MJ, Rosen N, Scher HI (2007) Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer. Clin Cancer Res 13(6):1775–1782. doi:10.1158/1078-0432.CCR-06-1863

    CAS  PubMed Central  PubMed  Google Scholar 

  44. 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 56(2):115–125. doi:10.1007/s00280-004-0939-2

    CAS  PubMed  Google Scholar 

  45. Ge J, Normant E, Porter JR, Ali JA, Dembski MS, Gao Y, Georges AT, Grenier L, Pak RH, Patterson J, Sydor JR, Tibbitts TT, Tong JK, Adams J, Palombella VJ (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(15):4606–4615. doi:10.1021/jm0603116

    CAS  PubMed  Google Scholar 

  46. Sydor JR, Normant E, Pien CS, Porter JR, Ge J, Grenier L, Pak RH, Ali JA, Dembski MS, Hudak J, Patterson J, Penders C, Pink M, Read MA, Sang J, Woodward C, Zhang Y, Grayzel DS, Wright J, Barrett JA, Palombella VJ, Adams J, Tong JK (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(46):17408–17413. doi:10.1073/pnas.0608372103

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Sequist LV, Gettinger S, Senzer NN, Martins RG, Janne PA, Lilenbaum R, Gray JE, Iafrate AJ, Katayama R, Hafeez N, Sweeney J, Walker JR, Fritz C, Ross RW, Grayzel D, Engelman JA, Borger DR, Paez G, Natale R (2010) Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol 28(33):4953–4960. doi:10.1200/JCO.2010.30.8338

    CAS  PubMed  Google Scholar 

  48. Floris G, Debiec-Rychter M, Wozniak A, Stefan C, Normant E, Faa G, Machiels K, Vanleeuw U, Sciot R, Schoffski P (2011) The heat shock protein 90 inhibitor IPI-504 induces KIT degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors. Mol Cancer Ther 10(10):1897–1908. doi:10.1158/1535-7163.MCT-11-0148

    CAS  PubMed  Google Scholar 

  49. Soga S, Akinaga S, Shiotsu Y (2013) Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development. Curr Pharm Des 19(3):366–376

    CAS  PubMed  Google Scholar 

  50. Delmotte P, Delmotte-Plaque J (1953) A new antifungal substance of fungal origin. Nature 171(4347):344

    CAS  PubMed  Google Scholar 

  51. Schulte TW, Akinaga S, Soga S, Sullivan W, Stensgard B, Toft D, Neckers LM (1998) Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin. Cell Stress Chaperones 3(2):100–108

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Soga S, Neckers LM, Schulte TW, Shiotsu Y, Akasaka K, Narumi H, Agatsuma T, Ikuina Y, Murakata C, Tamaoki T, Akinaga S (1999) KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules. Cancer Res 59(12):2931–2938

    CAS  PubMed  Google Scholar 

  53. Yang ZQ, Geng X, Solit D, Pratilas CA, Rosen N, Danishefsky SJ (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(25):7881–7889. doi:10.1021/ja0484348

    CAS  PubMed  Google Scholar 

  54. Soga S, Shiotsu Y, Akinaga S, Sharma SV (2003) Development of radicicol analogues. Curr Cancer Drug Targets 3(5):359–369

    CAS  PubMed  Google Scholar 

  55. Blagg BS, Kerr TD (2006) Hsp90 inhibitors: small molecules that transform the Hsp90 protein folding machinery into a catalyst for protein degradation. Med Res Rev 26(3):310–338. doi:10.1002/med.20052

    CAS  PubMed  Google Scholar 

  56. Agatsuma T, Ogawa H, Akasaka K, Asai A, Yamashita Y, Mizukami T, Akinaga S, Saitoh Y (2002) Halohydrin and oxime derivatives of radicicol: synthesis and antitumor activities. Bioorg Med Chem 10(11):3445–3454

    CAS  PubMed  Google Scholar 

  57. Ikuina Y, Amishiro N, Miyata M, Narumi H, Ogawa H, Akiyama T, Shiotsu Y, Akinaga S, Murakata C (2003) Synthesis and antitumor activity of novel O-carbamoylmethyloxime derivatives of radicicol. J Med Chem 46(12):2534–2541. doi:10.1021/jm030110r

    CAS  PubMed  Google Scholar 

  58. 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(2):176–183. doi:10.1016/j.ab.2003.10.038

    CAS  PubMed  Google Scholar 

  59. Cheung KM, Matthews TP, James K, Rowlands MG, Boxall KJ, Sharp SY, Maloney A, Roe SM, Prodromou C, Pearl LH, Aherne GW, McDonald E, Workman P (2005) The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors. Bioorg Med Chem Lett 15(14):3338–3343. doi:10.1016/j.bmcl.2005.05.046

    CAS  PubMed  Google Scholar 

  60. 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(13):4212–4215. doi:10.1021/jm050355z

    CAS  PubMed  Google Scholar 

  61. Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung KM, Collins I, Davies NG, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wright L (2008) 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 51(2):196–218. doi:10.1021/jm701018h

    CAS  PubMed  Google Scholar 

  62. Brough PA, Barril X, Beswick M, Dymock BW, Drysdale MJ, Wright L, Grant K, Massey A, Surgenor A, Workman P (2005) 3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone. Bioorg Med Chem Lett 15(23):5197–5201. doi:10.1016/j.bmcl.2005.08.091

    CAS  PubMed  Google Scholar 

  63. Barril X, Beswick MC, Collier A, Drysdale MJ, Dymock BW, Fink A, Grant K, Howes R, Jordan AM, Massey A, Surgenor A, Wayne J, Workman P, Wright L (2006) 4-Amino derivatives of the Hsp90 inhibitor CCT018159. Bioorg Med Chem Lett 16(9):2543–2548. doi:10.1016/j.bmcl.2006.01.099

    CAS  PubMed  Google Scholar 

  64. Sharp SY, Prodromou C, Boxall K, Powers MV, Holmes JL, Box G, Matthews TP, Cheung KM, Kalusa A, James K, Hayes A, Hardcastle A, Dymock B, Brough PA, Barril X, Cansfield JE, Wright L, Surgenor A, Foloppe N, Hubbard RE, Aherne W, Pearl L, Jones K, McDonald E, Raynaud F, Eccles S, Drysdale M, Workman P (2007) Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues. Mol Cancer Ther 6(4):1198–1211. doi:10.1158/1535-7163.MCT-07-0149

    CAS  PubMed  Google Scholar 

  65. Jensen MR, Schoepfer J, Radimerski T, Massey A, Guy CT, Brueggen J, Quadt C, Buckler A, Cozens R, Drysdale MJ, Garcia-Echeverria C, Chene P (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10(2):R33. doi:10.1186/bcr1996

    PubMed Central  PubMed  Google Scholar 

  66. Sessa C, Shapiro GI, Bhalla KN, Britten C, Jacks KS, Mita M, Papadimitrakopoulou V, Pluard T, Samuel TA, Akimov M, Quadt C, Fernandez-Ibarra C, Lu H, Bailey S, Chica S, Banerji U (2013) First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res 19(13):3671–3680. doi:10.1158/1078-0432.CCR-12-3404

    CAS  PubMed  Google Scholar 

  67. Murray CW, Carr MG, Callaghan O, Chessari G, Congreve M, Cowan S, Coyle JE, Downham R, Figueroa E, Frederickson M, Graham B, McMenamin R, O’Brien MA, Patel S, Phillips TR, Williams G, Woodhead AJ, Woolford AJ (2010) Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency. J Med Chem 53(16):5942–5955. doi:10.1021/jm100059d

    CAS  PubMed  Google Scholar 

  68. Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O’Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ (2010) Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydrois oindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem 53(16):5956–5969. doi:10.1021/jm100060b

    CAS  PubMed  Google Scholar 

  69. Graham B, Curry J, Smyth T, Fazal L, Feltell R, Harada I, Coyle J, Williams B, Reule M, Angove H, Cross DM, Lyons J, Wallis NG, Thompson NT (2012) The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer. Cancer Sci 103(3):522–527. doi:10.1111/j.1349-7006.2011.02191.x

    CAS  PubMed  Google Scholar 

  70. El-Hariry I, Proia D, Vukovic V (2013) Treating cancer with heat-shock protein-90 (HSP90) inhibitory compounds such as ganetespib. WO2013006864A2

    Google Scholar 

  71. Ying W, Du Z, Sun L, Foley KP, Proia DA, Blackman RK, Zhou D, Inoue T, Tatsuta N, Sang J, Ye S, Acquaviva J, Ogawa LS, Wada Y, Barsoum J, Koya K (2012) Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy. Mol Cancer Ther 11(2):475–484. doi:10.1158/1535-7163.MCT-11-0755

    CAS  PubMed  Google Scholar 

  72. Goldman JW, Raju RN, Gordon GA, El-Hariry I, Teofilivici F, Vukovic VM, Bradley R, Karol MD, Chen Y, Guo W, Inoue T, Rosen LS (2013) A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies. BMC Cancer 13:152. doi:10.1186/1471-2407-13-152

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Socinski MA, Goldman J, El-Hariry I, Koczywas M, Vukovic V, Horn L, Paschold E, Salgia R, West H, Sequist LV, Bonomi P, Brahmer J, Chen LC, Sandler A, Belani CP, Webb T, Harper H, Huberman M, Ramalingam S, Wong KK, Teofilovici F, Guo W, Shapiro GI (2013) A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer. Clin Cancer Res 19(11):3068–3077. doi:10.1158/1078-0432.CCR-12-3381

    CAS  PubMed  Google Scholar 

  74. Nakashima T, Ishii T, Tagaya H, Seike T, Nakagawa H, Kanda Y, Akinaga S, Soga S, Shiotsu Y (2010) New molecular and biological mechanism of antitumor activities of KW-2478, a novel nonansamycin heat shock protein 90 inhibitor, in multiple myeloma cells. Clin Cancer Res 16(10):2792–2802. doi:10.1158/1078-0432.CCR-09-3112

    CAS  PubMed  Google Scholar 

  75. Dutta R, Inouye M (2000) GHKL, an emergent ATPase/kinase superfamily. Trends Biochem Sci 25(1):24–28

    CAS  PubMed  Google Scholar 

  76. Chene P (2002) ATPases as drug targets: learning from their structure. Nat Rev Drug Discov 1(9):665–673. doi:10.1038/nrd894

    CAS  PubMed  Google Scholar 

  77. Chiosis G, Timaul MN, Lucas B, Munster PN, Zheng FF, Sepp-Lorenzino L, Rosen N (2001) A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells. Chem Biol 8(3):289–299. doi:S1074-5521(01)00015-1

    CAS  PubMed  Google Scholar 

  78. 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(6):775–785. doi:10.1016/j.chembiol.2004.03.033

    CAS  PubMed  Google Scholar 

  79. He H, Zatorska D, Kim J, Aguirre J, Llauger L, She Y, Wu N, Immormino RM, Gewirth DT, Chiosis G (2006) Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. J Med Chem 49(1):381–390. doi:10.1021/jm0508078

    CAS  PubMed  Google Scholar 

  80. 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(11):3555–3564

    CAS  PubMed  Google Scholar 

  81. Dymock B, Barril X, Beswick M, Collier A, Davies N, Drysdale M, Fink A, Fromont C, Hubbard RE, Massey A, Surgenor A, Wright L (2004) Adenine derived inhibitors of the molecular chaperone HSP90-SAR explained through multiple X-ray structures. Bioorg Med Chem Lett 14(2):325–328

    CAS  PubMed  Google Scholar 

  82. Kim J, Felts S, Llauger L, He H, Huezo H, Rosen N, Chiosis G (2004) Development of a fluorescence polarization assay for the molecular chaperone Hsp90. J Biomol Screen 9(5):375–381. doi:10.1177/1087057104265995

    CAS  PubMed  Google Scholar 

  83. 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(8):2892–2905. doi:10.1021/jm049012b

    CAS  PubMed  Google Scholar 

  84. Llauger-Bufi L, Felts SJ, Huezo H, Rosen N, Chiosis G (2003) Synthesis of novel fluorescent probes for the molecular chaperone Hsp90. Bioorg Med Chem Lett 13(22):3975–3978

    CAS  PubMed  Google Scholar 

  85. Biamonte MA, Shi J, Hong K, Hurst DC, Zhang L, Fan J, Busch DJ, Karjian PL, Maldonado AA, Sensintaffar JL, Yang YC, Kamal A, Lough RE, Lundgren K, Burrows FJ, Timony GA, Boehm MF, Kasibhatla SR (2006) Orally active purine-based inhibitors of the heat shock protein 90. J Med Chem 49(2):817–828. doi:10.1021/jm0503087

    CAS  PubMed  Google Scholar 

  86. He H, Llauger L, Rosen N, Chiosis G (2004) General method for the synthesis of 8-arylsulfanyl adenine derivatives. J Org Chem 69(9):3230–3232. doi:10.1021/jo049875c

    CAS  PubMed  Google Scholar 

  87. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A, Moulick K, Taldone T, Gozman A, Guo Y, Wu N, de Stanchina E, White J, Gross SS, Ma Y, Varticovski L, Melnick A, Chiosis G (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci U S A 106(20):8368–8373. doi:10.1073/pnas.0903392106

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC, Kang Y, She Y, Wu N, Felts S, Wipf P, Massague J, Jiang X, Brodsky JL, Krystal GW, Chiosis G (2007) Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol 3(8):498–507. doi:10.1038/nchembio.2007.10

    CAS  PubMed  Google Scholar 

  89. Breinig M, Caldas-Lopes E, Goeppert B, Malz M, Rieker R, Bergmann F, Schirmacher P, Mayer M, Chiosis G, Kern MA (2009) Targeting heat shock protein 90 with non-quinone inhibitors: a novel chemotherapeutic approach in human hepatocellular carcinoma. Hepatology 50 (1):102–112. doi:10.1002/hep. 22912

    CAS  PubMed  Google Scholar 

  90. Cerchietti LC, Lopes EC, Yang SN, Hatzi K, Bunting KL, Tsikitas LA, Mallik A, Robles AI, Walling J, Varticovski L, Shaknovich R, Bhalla KN, Chiosis G, Melnick A (2009) A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas. Nat Med 15(12):1369–1376. doi:10.1038/nm.2059

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Marubayashi S, Koppikar P, Taldone T, Abdel-Wahab O, West N, Bhagwat N, Caldas-Lopes E, Ross KN, Gonen M, Gozman A, Ahn JH, Rodina A, Ouerfelli O, Yang G, Hedvat C, Bradner JE, Chiosis G, Levine RL (2010) HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest 120(10):3578–3593. doi:10.1172/JCI42442

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Kim SH, Bajji A, Tangallapally R, Markovitz B, Trovato R, Shenderovich M, Baichwal V, Bartel P, Cimbora D, McKinnon R, Robinson R, Papac D, Wettstein D, Carlson R, Yager KM (2012) Discovery of (2 S)-1-[4-(2-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9 H-purin-9-yl}ethyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a purine-based Hsp90 inhibitor. J Med Chem 55(17):7480–7501. doi:10.1021/jm3004619

    CAS  PubMed  Google Scholar 

  93. Bajji AC, Tangallapally RP, Kim IC, Kim SH, Parker DP, Trovato R, Papac DI, Yager K, Baichwal VR (2012) Preparation of 6-amino-9 H-purine prodrugs as HSP90 inhibitors for the treatment of cancer. WO2012148550A1

    Google Scholar 

  94. 10-Q: MYREXIS, INC (2012). http://www.marketwatch.com/story/10-q-myrexis-inc-2012-11-09. Accessed 8 Oct 2013

  95. Cai X, Zhai H-X, Wang J, Samson M, Atoyan R, Forrester J, Qu H, Yin L, Wang D, Zifcak B, DellaRocca S, Xu G-X, Lai C-J, Bao R, Simonin M-P, Keegan M, Pepicelli CV, Changgeng Q (2011) Design and synthesis of imidazopyridine derivatives as novel HSP90 inhibitors for the treatment of cancer. Proceedings: AACR 102nd Annual Meeting 2011, Apr 2–6, Orlando, Florida. doi:10.1158/1538-7445.AM2011-3249

    Google Scholar 

  96. Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B, Atoyan R, Wang J, Samson M, Forrester J, DellaRocca S, Xu GX, Tao X, Zhai HX, Cai X, Qian C (2009) CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res 15(12):4046–4057. doi:10.1158/1078-0432.CCR-09-0152

    CAS  PubMed  Google Scholar 

  97. Curis (2013) Debio 0932. http://www.curis.com/pipeline_detail.php?id=15. Accessed 21 Sept 2013

  98. Kasibhatla SR, Hong K, Biamonte MA, Busch DJ, Karjian PL, Sensintaffar JL, Kamal A, Lough RE, Brekken J, Lundgren K, Grecko R, Timony GA, Ran Y, Mansfield R, Fritz LC, Ulm E, Burrows FJ, Boehm MF (2007) Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity. J Med Chem 50(12):2767–2778. doi:10.1021/jm050752+

    CAS  PubMed  Google Scholar 

  99. Lundgren K, Zhang H, Brekken J, Huser N, Powell RE, Timple N, Busch DJ, Neely L, Sensintaffar JL, Yang YC, McKenzie A, Friedman J, Scannevin R, Kamal A, Hong K, Kasibhatla SR, Boehm MF, Burrows FJ (2009) BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90. Mol Cancer Ther 8(4):921–929. doi:10.1158/1535-7163.MCT-08-0758

    CAS  PubMed  Google Scholar 

  100. Dickson MA, Okuno SH, Keohan ML, Maki RG, D’Adamo DR, Akhurst TJ, Antonescu CR, Schwartz GK (2013) Phase II study of the HSP90-inhibitor BIIB021 in gastrointestinal stromal tumors. Ann Oncol 24(1):252–257. doi:10.1093/annonc/mds275

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Mitchell P (2011) Biogen Idec restructures, sharpens neurology focus. Nat Biotechnol 29(1):7–8. doi:10.1038/nbt0111-7

    CAS  PubMed  Google Scholar 

  102. Fadden P, Huang KH, Veal JM, Steed PM, Barabasz AF, Foley B, Hu M, Partridge JM, Rice J, Scott A, Dubois LG, Freed TA, Silinski MA, Barta TE, Hughes PF, Ommen A, Ma W, Smith ED, Spangenberg AW, Eaves J, Hanson GJ, Hinkley L, Jenks M, Lewis M, Otto J, Pronk GJ, Verleysen K, Haystead TA, Hall SE (2010) Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90. Chem Biol 17(7):686–694. doi:10.1016/j.chembiol.2010.04.015

    CAS  PubMed  Google Scholar 

  103. Huang KH, Veal JM, Fadden RP, Rice JW, Eaves J, Strachan JP, Barabasz AF, Foley BE, Barta TE, Ma W, Silinski MA, Hu M, Partridge JM, Scott A, DuBois LG, Freed T, Steed PM, Ommen AJ, Smith ED, Hughes PF, Woodward AR, Hanson GJ, McCall WS, Markworth CJ, Hinkley L, Jenks M, Geng L, Lewis M, Otto J, Pronk B, Verleysen K, Hall SE (2009) Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents. J Med Chem 52(14):4288–4305. doi:10.1021/jm900230j

    CAS  PubMed  Google Scholar 

  104. Rajan A, Kelly RJ, Trepel JB, Kim YS, Alarcon SV, Kummar S, Gutierrez M, Crandon S, Zein WM, Jain L, Mannargudi B, Figg WD, Houk BE, Shnaidman M, Brega N, Giaccone G (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(21):6831–6839. doi:10.1158/1078-0432.CCR-11-0821

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Menezes DL, Taverna P, Jensen MR, Abrams T, Stuart D, Yu GK, Duhl D, Machajewski T, Sellers WR, Pryer NK, Gao Z (2012) The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo. Mol Cancer Ther 11(3):730–739. doi:10.1158/1535-7163.MCT-11-0667

    CAS  PubMed  Google Scholar 

  106. Vernalis (2012) Interim results for the six months ended 30 June 2012. http://www.vernalis.com/media-centre/latest-releases/2012-releases/642-interim-results-for-the-six-months-ended-30-june-2012. Accessed 21 Sept 2013

  107. Bussenius J, Blazey CM, Aay N, Anand NK, Arcalas A, Baik T, Bowles OJ, Buhr CA, Costanzo S, Curtis JK, DeFina SC, Dubenko L, Heuer TS, Huang P, Jaeger C, Joshi A, Kennedy AR, Kim AI, Lara K, Lee J, Li J, Lougheed JC, Ma S, Malek S, Manalo JC, Martini JF, McGrath G, Nicoll M, Nuss JM, Pack M, Peto CJ, Tsang TH, Wang L, Womble SW, Yakes M, Zhang W, Rice KD (2012) Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90. Bioorg Med Chem Lett 22(17):5396–5404. doi:10.1016/j.bmcl.2012.07.052

    CAS  PubMed  Google Scholar 

  108. Paraiso KH, Haarberg HE, Wood E, Rebecca VW, Chen YA, Xiang Y, Ribas A, Lo RS, Weber JS, Sondak VK, John JK, Sarnaik AA, Koomen JM, Smalley KS (2012) The HSP90 inhibitor XL888 overcomes BRAF inhibitor resistance mediated through diverse mechanisms. Clin Cancer Res 18(9):2502–2514. doi:10.1158/1078-0432.CCR-11-2612

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Study of XL888 With Vemurafenib for patients with unresectable BRAF mutated stage III/IV melanoma. U.S. National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01657591?term=XL888&rank=2. Accessed 5 July 2013

  110. Taldone T, Patel PD, Patel M, Patel HJ, Evans CE, Rodina A, Ochiana S, Shah SK, Uddin M, Gewirth D, Chiosis G (2013) Experimental and structural testing module to analyze paralogue-specificity and affinity in the Hsp90 inhibitors series. J Med Chem 56(17):6803–6818. doi:10.1021/jm400619b

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Patel PD, Yan P, Seidler PM, Patel HJ, Sun W, Yang C, Que NS, Taldone T, Finotti P, Stephani RA, Gewirth DT, Chiosis G (2013) Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol 9(11):677 − 684.doi:10.1038/nchembio.1335

    CAS  PubMed  Google Scholar 

  112. Kang BH, Plescia J, Dohi T, Rosa J, Doxsey SJ, Altieri DC (2007) Regulation of tumor cell mitochondrial homeostasis by an organelle-specific Hsp90 chaperone network. Cell 131(2):257–270. doi:10.1016/j.cell.2007.08.028

    CAS  PubMed  Google Scholar 

  113. Altieri DC, Stein GS, Lian JB, Languino LR (2012) TRAP-1, the mitochondrial Hsp90. Biochim Biophys Acta 1823(3):767–773. doi:10.1016/j.bbamcr.2011.08.007

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Kang BH, Plescia J, Song HY, Meli M, Colombo G, Beebe K, Scroggins B, Neckers L, Altieri DC (2009) Combinatorial drug design targeting multiple cancer signaling networks controlled by mitochondrial Hsp90. J Clin Invest 119(3):454–464. doi:10.1172/JCI37613

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Kang BH, Siegelin MD, Plescia J, Raskett CM, Garlick DS, Dohi T, Lian JB, Stein GS, Languino LR, Altieri DC (2010) Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer. Clin Cancer Res 16(19):4779–4788. doi:10.1158/1078-0432.CCR-10-1818

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Marzec M, Eletto D, Argon Y (2012) GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim Biophys Acta 1823(3):774–787. doi:10.1016/j.bbamcr.2011.10.013

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Zheng H, Dai J, Stoilova D, Li Z (2001) Cell surface targeting of heat shock protein gp96 induces dendritic cell maturation and antitumor immunity. J Immunol 167(12):6731–6735

    CAS  PubMed  Google Scholar 

  118. Ni M, Lee AS (2007) ER chaperones in mammalian development and human diseases. FEBS Lett 581(19):3641–3651. doi:10.1016/j.febslet.2007.04.045

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Eletto D, Dersh D, Argon Y (2010) GRP94 in ER quality control and stress responses. Semin Cell Dev Biol 21(5):479–485. doi:10.1016/j.semcdb.2010.03.004

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Duerfeldt AS, Peterson LB, Maynard JC, Ng CL, Eletto D, Ostrovsky O, Shinogle HE, Moore DS, Argon Y, Nicchitta CV, Blagg BS (2012) Development of a Grp94 inhibitor. J Am Chem Soc 134(23):9796–9804. doi:10.1021/ja303477g

    CAS  PubMed Central  PubMed  Google Scholar 

  121. 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(47):37181–37186. doi:10.1074/jbc.M003701200

    CAS  PubMed  Google Scholar 

  122. Centenera MM, Fitzpatrick AK, Tilley WD, Butler LM (2013) Hsp90: still a viable target in prostate cancer. Biochim Biophys Acta 1835(2):211–218. doi:10.1016/j.bbcan.2012.12.005

    CAS  PubMed  Google Scholar 

  123. Eskew JD, Sadikot T, Morales P, Duren A, Dunwiddie I, Swink M, Zhang X, Hembruff S, Donnelly A, Rajewski RA, Blagg BS, Manjarrez JR, Matts RL, Holzbeierlein JM, Vielhauer GA (2011) Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells. BMC Cancer 11:468. doi:10.1186/1471-2407-11-468

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Matthews SB, Vielhauer GA, Manthe CA, Chaguturu VK, Szabla K, Matts RL, Donnelly AC, Blagg BS, Holzbeierlein JM (2010) Characterization of a novel novobiocin analogue as a putative C-terminal inhibitor of heat shock protein 90 in prostate cancer cells. Prostate 70(1):27–36. doi:10.1002/pros.21035

    CAS  PubMed  Google Scholar 

  125. Palermo CM, Westlake CA, Gasiewicz TA (2005) Epigallocatechin gallate inhibits aryl hydrocarbon receptor gene transcription through an indirect mechanism involving binding to a 90 kDa heat shock protein. BioChemistry 44(13):5041–5052. doi:10.1021/bi047433p

    CAS  PubMed  Google Scholar 

  126. Khandelwal A, Hall J, Blagg BS (2013) Synthesis and structure-activity relationships of egcg analogues, a recently identified Hsp90 inhibitor. J Org Chem 78(16):7859 − 7884.doi:10.1021/jo401027r

    CAS  PubMed Central  PubMed  Google Scholar 

  127. 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(10):1991–2001. doi:10.1210/me.2003-0141

    CAS  PubMed  Google Scholar 

  128. Chaudhury S, Welch TR, Blagg BS (2006) Hsp90 as a target for drug development. ChemMedChem 1(12):1331–1340. doi:10.1002/cmdc.200600112

    CAS  PubMed  Google Scholar 

  129. Yu Y, Hamza A, Zhang T, Gu M, Zou P, Newman B, Li Y, Gunatilaka AA, Zhan CG, Sun D (2010) Withaferin A targets heat shock protein 90 in pancreatic cancer cells. Biochem Pharmacol 79 (4):542–551. doi:10.1016/j.bcp. 2009.09.017

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC, Sessa WC, Altieri DC (2003) Regulation of survivin function by Hsp90. Proc Natl Acad Sci U S A 100(24):13791–13796. doi:10.1073/pnas.2434345100

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Meli M, Pennati M, Curto M, Daidone MG, Plescia J, Toba S, Altieri DC, Zaffaroni N, Colombo G (2006) Small-molecule targeting of heat shock protein 90 chaperone function: rational identification of a new anticancer lead. J Med Chem 49(26):7721–7730. doi:10.1021/jm060836y

    CAS  PubMed  Google Scholar 

  132. Plescia J, Salz W, Xia F, Pennati M, Zaffaroni N, Daidone MG, Meli M, Dohi T, Fortugno P, Nefedova Y, Gabrilovich DI, Colombo G, Altieri DC (2005) Rational design of shepherdin, a novel anticancer agent. Cancer Cell 7(5):457–468. doi:10.1016/j.ccr.2005.03.035

    CAS  PubMed  Google Scholar 

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  1. Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Stefan O. Ochiana PhD, Tony Taldone PhD & Gabriela Chiosis PhD

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    Walid A. Houry

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Ochiana, S., Taldone, T., Chiosis, G. (2014). Designing Drugs Against Hsp90 for Cancer Therapy. In: Houry, W. (eds) The Molecular Chaperones Interaction Networks in Protein Folding and Degradation. Interactomics and Systems Biology, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1130-1_7

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