Targeting the C-Terminus of Hsp90 as a Cancer Therapy

Part of the Topics in Medicinal Chemistry book series (TMC, volume 19)


Classical Hsp90 inhibitors target the N-terminal ATP binding site. While these inhibitors have had some clinical success, treatment with these molecules leads to a dramatic increase in a set of stress-related proteins, a response that is referred to as a heat shock response. The induction of a heat shock response protects the cell against the protein aggregation induced by inhibiting Hsp90 and slows down cell death. Alternatively, inhibiting Hsp90 by modulating the C-terminus does not lead to a heat shock response. Current efforts to inhibit Hsp90’s C-terminus include molecules derived from natural products and mimics of native Hsp90-binding proteins. This diverse effort toward new C-terminal modulators of Hsp90 and their promising biological profile suggests that this strategy is likely the most productive future for targeting Hsp90.


ATP binding inhibitors Cancer C-terminus Heat shock proteins Hsp90 Natural products Natural product small molecules 


  1. 1.
    Izar B, Rotow J, Gainor J, Clark J, Chabner B (2013) Pharmacokinetics, clinical indications, and resistance mechanisms in molecular targeted therapies in cancer. Pharmacol Rev 65:1351–1395CrossRefGoogle Scholar
  2. 2.
    Bagatell R, Whitesell L (2004) Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther 3:1021–1030CrossRefGoogle Scholar
  3. 3.
    Trepel J, Mollapour M, Giaccone G et al (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537–549CrossRefGoogle Scholar
  4. 4.
    Miyata Y, Nakamoto H, Neckers L (2013) The therapeutic target hsp90 and cancer hallmarks. Curr Pharm Des 19:347–365CrossRefGoogle Scholar
  5. 5.
    Whitesell L, Mimnaugh EG, De Costa B et al (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 91:8324–8328CrossRefGoogle Scholar
  6. 6.
    Jhaveri K, Modi S (2012) HSP90 inhibitors for cancer therapy and overcoming drug resistance. Adv Pharmacol 65:471–517CrossRefGoogle Scholar
  7. 7.
    Jhaveri K, Taldone T, Modi S et al (2012) Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 1823:742–755CrossRefGoogle Scholar
  8. 8.
    Pacey S, Wilson RH, Walton M et al (2011) A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin Cancer Res 17:1561–1570CrossRefGoogle Scholar
  9. 9.
    Modi S, Stopeck A, Linden H et al (2011) HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab. Clin Cancer Res 17:5132–5139CrossRefGoogle Scholar
  10. 10.
    Sequist LV, Gettinger S, Senzer NN et al (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 28:4953–4960CrossRefGoogle Scholar
  11. 11.
    Lancet JE, Gojo I, Burton M 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 24:699–705CrossRefGoogle Scholar
  12. 12.
    Rajan A, Kelly RJ, Trepel JB 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 17:6831–6839CrossRefGoogle Scholar
  13. 13.
    Sydor JR, Normant E, Pien CS 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 103:17408–17413CrossRefGoogle Scholar
  14. 14.
    Bagatell R, Paine-Murrieta GD, Taylor CW et al (2000) Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of hsp90-binding agents. Clin Cancer Res 6:3312–3318Google Scholar
  15. 15.
    Wang Y, McAlpine SR (2015) C-terminal heat shock protein 90 modulators produce desirable oncogenic properties. Org Biomol Chem 13:4627–4631CrossRefGoogle Scholar
  16. 16.
    Wang Y, McAlpine SR (2015) Combining an Hsp70 inhibitor with either an N-terminal and C-terminal hsp90 inhibitor produces mechanistically distinct phenotypes. Org Biomol Chem 13:3691–3698CrossRefGoogle Scholar
  17. 17.
    Wang Y, McAlpine SR (2015) Heat shock protein 90 inhibitors: will they ever succeed as chemotherapeutics? Future Med Chem 7:87–90CrossRefGoogle Scholar
  18. 18.
    Wang Y, Mcalpine SR (2015) N-terminal and C-terminal modulation of Hsp90 produce dissimilar phenotypes. Chem Comm 51:1410–1413CrossRefGoogle Scholar
  19. 19.
    Wang Y, McAlpine SR (2015) Regulating the cytoprotective response in cancer cells using simultaneous inhibition of Hsp90 and Hsp70. Org Biomol Chem 13:2108–2116CrossRefGoogle Scholar
  20. 20.
    Wang Y, Islam A, Davis RA et al (2015) The fungal natural product (1S, 3S)-austrocortirubin induces DNA damage via a mechanism unique from other DNA damaging agents. Bioorg Med Chem Lett 25:249–253CrossRefGoogle Scholar
  21. 21.
    Eskew JD, Sadikot T, Morales P et al (2011) Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells. Bio Med Central Cancer 11:468Google Scholar
  22. 22.
    Allan RK, Mok D, Ward BK et al (2006) Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90. J Biol Chem 281:7161–7171CrossRefGoogle Scholar
  23. 23.
    McConnell JM, Alexander LD, McAlpine SR (2014) A heat shock protein inhibitor that modulates immunophilins and regulates hormone receptors. Bioorg Med Chem Lett 24:661–666CrossRefGoogle Scholar
  24. 24.
    Koay YC, McConnell JR, Wang Y et al (2014) Chemically accessible Hsp90 inhibitor that does not induce a heat shock response. ACS Med Chem Lett 5:771–776CrossRefGoogle Scholar
  25. 25.
    Powers MV, Clarke PA, Workman P (2009) Death by chaperone: HSP90, HSP70 or both? Cell Cycle 8:518–526CrossRefGoogle Scholar
  26. 26.
    Zhang H, Chung D, Yang YC et al (2006) Identification of new biomarkers for clinical trials of Hsp90 inhibitors. Mol Cancer Ther 5:1256–1264CrossRefGoogle Scholar
  27. 27.
    Song D, Chaerkady R, Tan AC et al (2008) Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer. Mol Cancer Ther 7:3275–3284CrossRefGoogle Scholar
  28. 28.
    Calderwood SK, Khaleque MA, Sawyer DB et al (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31:164–172CrossRefGoogle Scholar
  29. 29.
    Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918CrossRefGoogle Scholar
  30. 30.
    McCollum AK, TenEyck CJ, Sauer BM et al (2006) Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Cancer Res 66:10967–10975CrossRefGoogle Scholar
  31. 31.
    Maloney A, Clarke PA, Naaby-Hansen S et al (2007) Gene and protein expression profiling of human ovarian cancer cells treated with the heat shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin. Cancer Res 67:3239–3253CrossRefGoogle Scholar
  32. 32.
    Caldas-Lopes E, Cerchietti L, Ahn JH et al (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 106:8368–8373CrossRefGoogle Scholar
  33. 33.
    Gaspar N, Sharp SY, Eccles SA et al (2010) Mechanistic evaluation of the novel HSP90 inhibitor NVP-AUY922 in adult and pediatric glioblastoma. Mol Cancer Ther 9:1219–1233CrossRefGoogle Scholar
  34. 34.
    Chatterjee M, Andrulis M, Stühmer T et al (2013) The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma. Haematologica 98:1132–1141CrossRefGoogle Scholar
  35. 35.
    Powers MV, Clarke PA, Workman P (2008) Dual targeting of Hsc70 and Hsp72 inhibits Hsp90 function and induces tumor-specific apoptosis. Cancer Cell 14:250–262CrossRefGoogle Scholar
  36. 36.
    Stühmer T, Zöllinger A, Siegmund D et al (2008) Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma. Leukemia 22:1604–1612CrossRefGoogle Scholar
  37. 37.
    Stühmer T, Chatterjee M, Grella E et al (2009) Anti-myeloma activity of the novel 2-aminothienopyrimidine Hsp90 inhibitor NVP-BEP800. Br J Haematol 47:319–327CrossRefGoogle Scholar
  38. 38.
    Davenport EL, Zeisig A, Aronson LI et al (2010) Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma. Leukemia 24:1804–1807CrossRefGoogle Scholar
  39. 39.
    Ardi VC, Alexander LD, Johnson VA et al (2011) Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins. ACS Chem Biol 6:1357–1367CrossRefGoogle Scholar
  40. 40.
    Alexander LD, Partridge JR, Agard DA et al (2011) A small molecule that preferentially binds the closed Hsp90 conformation. Bioorg Med Chem Lett 21:7068–7071CrossRefGoogle Scholar
  41. 41.
    Vasko RC, Rodriguez RA, Cunningham CN et al (2010) Mechanistic studies of Sansalvamide A-Amide: an allosteric modulator of Hsp90. ACS Med Chem Lett 1:4–8CrossRefGoogle Scholar
  42. 42.
    Yu XM, Shen G, Cronk B et al (2005) Hsp90 inhibitors identified from a library of novobiocin analogues. J Am Chem Soc 127:12778–12779CrossRefGoogle Scholar
  43. 43.
    Kusuma BR, Peterson LB, Zhao H et al (2011) Targeting the heat shock protein 90 dimer with dimeric inhibitors. J Med Chem 54:6234–6253CrossRefGoogle Scholar
  44. 44.
    Mendillo ML, Santagata S, Koeva M et al (2012) HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers. Cell 150:549–562CrossRefGoogle Scholar
  45. 45.
    Gabai VL, Meng L, Kim G et al (2012) Heat shock transcription factor Hsf1 is involved in tumor progression via regulation of hypoxia-inducible factor 1 and RNA-binding protein HuR. Mol Cell Biol 32:929–940CrossRefGoogle Scholar
  46. 46.
    Santagata S, Hu R, Lin NU et al (2011) High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci U S A 108:18378–18383CrossRefGoogle Scholar
  47. 47.
    Meng L, Gabai VL, Sherman MY (2010) Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis. Oncogene 29:5204–5213CrossRefGoogle Scholar
  48. 48.
    Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124CrossRefGoogle Scholar
  49. 49.
    Whitesell L, Santagata S, Lin NU (2012) Inhibiting hsp90 to treat cancer: a strategy in evolution. Curr Mol Med 12:1108–1124CrossRefGoogle Scholar
  50. 50.
    Nylandsted J, Gyrd-Hansen M, Danielewicz A et al (2004) Heat shock protein 70 promotes cell survival by inhibiting lysosomal membrane permeabilization. J Exp Med 200:425–435CrossRefGoogle Scholar
  51. 51.
    Guo F, Sigua C, Bali P et al (2005) Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 105:1246–1255CrossRefGoogle Scholar
  52. 52.
    Creagh EM, Sheehan D, Cotter TG (2000) Heat shock proteins–modulators of apoptosis in tumour cells. Leukemia 14:1161–1173CrossRefGoogle Scholar
  53. 53.
    Beere HM (2004) “The stress of dying”: the role of heat shock proteins in the regulation of apoptosis. J Cell Sci 117:2641–2651CrossRefGoogle Scholar
  54. 54.
    Takayama S, Reed JC, Homma S (2003) Heat-shock proteins as regulators of apoptosis. Oncogene 22:9041–9047CrossRefGoogle Scholar
  55. 55.
    Saleh A, Srinivasula SM, Balkir L et al (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–483CrossRefGoogle Scholar
  56. 56.
    Beere HM, Wolf BB, Cain K et al (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol 2:469–475CrossRefGoogle Scholar
  57. 57.
    Jäättelä M, Wissing D, Kokholm K et al (1998) Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J 17:6124–6134CrossRefGoogle Scholar
  58. 58.
    Ravagnan L, Gurbuxani S, Susin SA et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843CrossRefGoogle Scholar
  59. 59.
    Gurbuxani S, Schmitt E, Cande C et al (2003) Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22:6669–6678CrossRefGoogle Scholar
  60. 60.
    Li J, Hu W, Lan Q (2012) The apoptosis-resistance in t-AUCB-treated glioblastoma cells depends on activation of Hsp27. J Neurooncol 110:187–194CrossRefGoogle Scholar
  61. 61.
    Bauer K, Nitsche U, Slotta-Huspenina J et al (2012) High HSP27 and HSP70 expression levels are independent adverse prognostic factors in primary resected colon cancer. Cell Oncol (Dordr) 35:197–205CrossRefGoogle Scholar
  62. 62.
    Acunzo J, Katsogiannou M, Rocchi P (2012) Small heat shock proteins HSP27 (HspB1), αB-crystallin (HspB5) and HSP22 (HspB8) as regulators of cell death. Int J Biochem Cell Biol 44:1622–1631CrossRefGoogle Scholar
  63. 63.
    Hsu HS, Lin JH, Huang WC et al (2011) Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27. Cancer 117:1516–1528CrossRefGoogle Scholar
  64. 64.
    Heinrich JC, Tuukkanen A, Schroeder M et al (2011) RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients. J Cancer Res Clin Oncol 137:1349–1361CrossRefGoogle Scholar
  65. 65.
    Kang SH, Kang KW, Kim KH et al (2008) Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability. BMC Cancer 8:286CrossRefGoogle Scholar
  66. 66.
    Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335CrossRefGoogle Scholar
  67. 67.
    Burlison J, Blagg B (2006) Synthesis and evaluation of Coumermycin A1 analogues that inhibit the hsp90 protein machinery. Org Lett 8:4555–4558CrossRefGoogle Scholar
  68. 68.
    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 70:27–36Google Scholar
  69. 69.
    Koay YC, McConnell JR, Wang Y et al (2015) Blocking the heat shock response and depleting HSF-1 levels through heat shock protein 90 (hsp90) inhibition: a significant advance on current hsp90 chemotherapies. RSC Adv. doi: 10.1039/C5RA07056B
  70. 70.
    Wahyudi H, Wang Y, McAlpine SR (2014) Utilizing a Dimerization strategy to inhibit the dimer protein Hsp90:Synthesis and biological activity of a sansalvamide A dimer. Org Biomol Chem 12:765–773CrossRefGoogle Scholar
  71. 71.
    Scheufler C, Brinker A, Bourenkov G et al (2000) Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell 101:199–210CrossRefGoogle Scholar
  72. 72.
    Alag R, Bharatham N, Dong A et al (2009) Crystallographic structure of the tetratricopeptide repeat domain of Plasmodium falciparum FKBP35 and its molecular interaction with Hsp90 C-terminal pentapeptide. Protein Sci 18:2115–2124CrossRefGoogle Scholar
  73. 73.
    Zeytuni N, Zarivach R (2012) Structural and functional discussion of the tetra-trico-peptide repeat, a protein interaction module. Structure 7:397–405CrossRefGoogle Scholar
  74. 74.
    Blatch GL, Lassle M (1999) The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. BioEssays 21:932–939CrossRefGoogle Scholar
  75. 75.
    Caplan AJ (2003) What is a co-chaperone? Cell Stress Chaperones 8:105–107CrossRefGoogle Scholar
  76. 76.
    Cortajarena AL, Yi F, Regan L (2008) Designed TPR modules as novel anticancer agents. ACS Chem Biol 3:161–166CrossRefGoogle Scholar
  77. 77.
    Main ER, Xiong Y, Cocco MJ et al (2003) Design of stable alpha-helical arrays from an idealized TPR motif. Structure 11:497–508CrossRefGoogle Scholar
  78. 78.
    Cortajarena AL, Kajander T, Pan W et al (2004) Protein design to understand peptide ligand recognition by tetratricopeptide repeat proteins. Protein Eng Des Sel 17:399–409CrossRefGoogle Scholar
  79. 79.
    Horibe T, Kohno M, Haramoto M et al (2011) Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent. J Transl Med 9:8CrossRefGoogle Scholar
  80. 80.
    Kabouridis PS (2003) Biological applications of protein transduction technology. Trends Biotechnol 21:498–503CrossRefGoogle Scholar
  81. 81.
    Salvesen GS, Duckett CS (2002) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3:401–410CrossRefGoogle Scholar
  82. 82.
    Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54CrossRefGoogle Scholar
  83. 83.
    Redlak MJ, Miller TA (2011) Targeting PI3K/Akt/HSP90 signaling sensitizes gastric cancer cells to deoxycholate-induced apoptosis. Dig Dis Sci 56:323–329CrossRefGoogle Scholar
  84. 84.
    Wu A, Wu B, Guo J et al (2011) Elevated expression of CDK4 in lung cancer. J Transl Med 9:38CrossRefGoogle Scholar
  85. 85.
    Horibe T, Kawamoto M, Kohno M et al (2012) Cytotoxic activity to acute myeloid leukemia cells by Antp-TPR hybrid peptide targeting Hsp90. J Biosci Bioeng 114:96–103CrossRefGoogle Scholar
  86. 86.
    Stupp R, Hegi ME, van den Bent MJ et al (2006) Changing paradigms–an update on the multidisciplinary management of malignant glioma. Oncologist 11:165–180CrossRefGoogle Scholar
  87. 87.
    Omuro AM, Faivre S, Raymond E (2007) Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther 6:1909–1919CrossRefGoogle Scholar
  88. 88.
    Collins V (2004) Brain tumours: classification and genes. J Neurol Neurosurg Psychiatry 75:ii2–ii11Google Scholar
  89. 89.
    Horibe T, Torisawa A, Kohno M et al (2012) Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells. Mol Cancer 11:59CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.School of ChemistryUniversity of New South WalesKensingtonAustralia

Personalised recommendations