Skip to main content
SpringerLink
Log in
Book cover

Heat Shock Protein Inhibitors pp 1–20Cite as

Targeting the C-Terminus of Hsp90 as a Cancer Therapy

  • Chapter
  • First Online:

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

Abstract

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.

This is a preview of subscription content, 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 EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   329.99
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

Learn about institutional subscriptions

References

  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 65:1351–1395

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Trepel J, Mollapour M, Giaccone G et al (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537–549

    Article  CAS  Google Scholar 

  4. Miyata Y, Nakamoto H, Neckers L (2013) The therapeutic target hsp90 and cancer hallmarks. Curr Pharm Des 19:347–365

    Article  CAS  Google Scholar 

  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 91:8324–8328

    Article  CAS  Google Scholar 

  6. Jhaveri K, Modi S (2012) HSP90 inhibitors for cancer therapy and overcoming drug resistance. Adv Pharmacol 65:471–517

    Article  CAS  Google Scholar 

  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 1823:742–755

    Article  CAS  Google Scholar 

  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 17:1561–1570

    Article  CAS  Google Scholar 

  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 17:5132–5139

    Article  CAS  Google Scholar 

  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 28:4953–4960

    Article  CAS  Google Scholar 

  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 24:699–705

    Article  CAS  Google Scholar 

  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 17:6831–6839

    Article  CAS  Google Scholar 

  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 103:17408–17413

    Article  CAS  Google Scholar 

  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 6:3312–3318

    CAS  Google Scholar 

  15. Wang Y, McAlpine SR (2015) C-terminal heat shock protein 90 modulators produce desirable oncogenic properties. Org Biomol Chem 13:4627–4631

    Article  CAS  Google Scholar 

  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 13:3691–3698

    Article  CAS  Google Scholar 

  17. Wang Y, McAlpine SR (2015) Heat shock protein 90 inhibitors: will they ever succeed as chemotherapeutics? Future Med Chem 7:87–90

    Article  Google Scholar 

  18. Wang Y, Mcalpine SR (2015) N-terminal and C-terminal modulation of Hsp90 produce dissimilar phenotypes. Chem Comm 51:1410–1413

    Article  CAS  Google Scholar 

  19. Wang Y, McAlpine SR (2015) Regulating the cytoprotective response in cancer cells using simultaneous inhibition of Hsp90 and Hsp70. Org Biomol Chem 13:2108–2116

    Article  CAS  Google Scholar 

  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 25:249–253

    Article  CAS  Google Scholar 

  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 11:468

    CAS  Google Scholar 

  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 281:7161–7171

    Article  CAS  Google Scholar 

  23. McConnell JM, Alexander LD, McAlpine SR (2014) A heat shock protein inhibitor that modulates immunophilins and regulates hormone receptors. Bioorg Med Chem Lett 24:661–666

    Article  CAS  Google Scholar 

  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 5:771–776

    Article  CAS  Google Scholar 

  25. Powers MV, Clarke PA, Workman P (2009) Death by chaperone: HSP90, HSP70 or both? Cell Cycle 8:518–526

    Article  CAS  Google Scholar 

  26. Zhang H, Chung D, Yang YC et al (2006) Identification of new biomarkers for clinical trials of Hsp90 inhibitors. Mol Cancer Ther 5:1256–1264

    Article  CAS  Google Scholar 

  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 7:3275–3284

    Article  CAS  Google Scholar 

  28. Calderwood SK, Khaleque MA, Sawyer DB et al (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31:164–172

    Article  CAS  Google Scholar 

  29. Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918

    Article  CAS  Google Scholar 

  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 66:10967–10975

    Article  CAS  Google Scholar 

  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 67:3239–3253

    Article  CAS  Google Scholar 

  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 106:8368–8373

    Article  CAS  Google Scholar 

  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 9:1219–1233

    Article  CAS  Google Scholar 

  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 98:1132–1141

    Article  CAS  Google Scholar 

  35. Powers MV, Clarke PA, Workman P (2008) Dual targeting of Hsc70 and Hsp72 inhibits Hsp90 function and induces tumor-specific apoptosis. Cancer Cell 14:250–262

    Article  CAS  Google Scholar 

  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 22:1604–1612

    Article  Google Scholar 

  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 47:319–327

    Article  Google Scholar 

  38. Davenport EL, Zeisig A, Aronson LI et al (2010) Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma. Leukemia 24:1804–1807

    Article  CAS  Google Scholar 

  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 6:1357–1367

    Article  CAS  Google Scholar 

  40. Alexander LD, Partridge JR, Agard DA et al (2011) A small molecule that preferentially binds the closed Hsp90 conformation. Bioorg Med Chem Lett 21:7068–7071

    Article  CAS  Google Scholar 

  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 1:4–8

    Article  CAS  Google Scholar 

  42. Yu XM, Shen G, Cronk B et al (2005) Hsp90 inhibitors identified from a library of novobiocin analogues. J Am Chem Soc 127:12778–12779

    Article  CAS  Google Scholar 

  43. Kusuma BR, Peterson LB, Zhao H et al (2011) Targeting the heat shock protein 90 dimer with dimeric inhibitors. J Med Chem 54:6234–6253

    Article  CAS  Google Scholar 

  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 150:549–562

    Article  CAS  Google Scholar 

  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 32:929–940

    Article  CAS  Google Scholar 

  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 108:18378–18383

    Article  CAS  Google Scholar 

  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 29:5204–5213

    Article  CAS  Google Scholar 

  48. Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124

    Article  CAS  Google Scholar 

  49. Whitesell L, Santagata S, Lin NU (2012) Inhibiting hsp90 to treat cancer: a strategy in evolution. Curr Mol Med 12:1108–1124

    Article  CAS  Google Scholar 

  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 200:425–435

    Article  CAS  Google Scholar 

  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 105:1246–1255

    Article  CAS  Google Scholar 

  52. Creagh EM, Sheehan D, Cotter TG (2000) Heat shock proteins–modulators of apoptosis in tumour cells. Leukemia 14:1161–1173

    Article  CAS  Google Scholar 

  53. Beere HM (2004) “The stress of dying”: the role of heat shock proteins in the regulation of apoptosis. J Cell Sci 117:2641–2651

    Article  CAS  Google Scholar 

  54. Takayama S, Reed JC, Homma S (2003) Heat-shock proteins as regulators of apoptosis. Oncogene 22:9041–9047

    Article  CAS  Google Scholar 

  55. Saleh A, Srinivasula SM, Balkir L et al (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–483

    Article  CAS  Google Scholar 

  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 2:469–475

    Article  CAS  Google Scholar 

  57. Jäättelä M, Wissing D, Kokholm K et al (1998) Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J 17:6124–6134

    Article  Google Scholar 

  58. Ravagnan L, Gurbuxani S, Susin SA et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843

    Article  CAS  Google Scholar 

  59. Gurbuxani S, Schmitt E, Cande C et al (2003) Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22:6669–6678

    Article  CAS  Google Scholar 

  60. Li J, Hu W, Lan Q (2012) The apoptosis-resistance in t-AUCB-treated glioblastoma cells depends on activation of Hsp27. J Neurooncol 110:187–194

    Article  Google Scholar 

  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) 35:197–205

    Article  CAS  Google Scholar 

  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 44:1622–1631

    Article  CAS  Google Scholar 

  63. Hsu HS, Lin JH, Huang WC et al (2011) Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27. Cancer 117:1516–1528

    Article  CAS  Google Scholar 

  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 137:1349–1361

    Article  Google Scholar 

  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 8:286

    Article  Google Scholar 

  66. Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335

    Article  CAS  Google Scholar 

  67. Burlison J, Blagg B (2006) Synthesis and evaluation of Coumermycin A1 analogues that inhibit the hsp90 protein machinery. Org Lett 8:4555–4558

    Article  Google Scholar 

  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 70:27–36

    Google Scholar 

  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. 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 12:765–773

    Article  CAS  Google Scholar 

  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 101:199–210

    Article  CAS  Google Scholar 

  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 18:2115–2124

    Article  CAS  Google Scholar 

  73. Zeytuni N, Zarivach R (2012) Structural and functional discussion of the tetra-trico-peptide repeat, a protein interaction module. Structure 7:397–405

    Article  Google Scholar 

  74. Blatch GL, Lassle M (1999) The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. BioEssays 21:932–939

    Article  CAS  Google Scholar 

  75. Caplan AJ (2003) What is a co-chaperone? Cell Stress Chaperones 8:105–107

    Article  Google Scholar 

  76. Cortajarena AL, Yi F, Regan L (2008) Designed TPR modules as novel anticancer agents. ACS Chem Biol 3:161–166

    Article  CAS  Google Scholar 

  77. Main ER, Xiong Y, Cocco MJ et al (2003) Design of stable alpha-helical arrays from an idealized TPR motif. Structure 11:497–508

    Article  CAS  Google Scholar 

  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 17:399–409

    Article  CAS  Google Scholar 

  79. Horibe T, Kohno M, Haramoto M et al (2011) Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent. J Transl Med 9:8

    Article  CAS  Google Scholar 

  80. Kabouridis PS (2003) Biological applications of protein transduction technology. Trends Biotechnol 21:498–503

    Article  CAS  Google Scholar 

  81. Salvesen GS, Duckett CS (2002) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3:401–410

    Article  CAS  Google Scholar 

  82. Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54

    Article  CAS  Google Scholar 

  83. Redlak MJ, Miller TA (2011) Targeting PI3K/Akt/HSP90 signaling sensitizes gastric cancer cells to deoxycholate-induced apoptosis. Dig Dis Sci 56:323–329

    Article  CAS  Google Scholar 

  84. Wu A, Wu B, Guo J et al (2011) Elevated expression of CDK4 in lung cancer. J Transl Med 9:38

    Article  CAS  Google Scholar 

  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 114:96–103

    Article  CAS  Google Scholar 

  86. Stupp R, Hegi ME, van den Bent MJ et al (2006) Changing paradigms–an update on the multidisciplinary management of malignant glioma. Oncologist 11:165–180

    Article  CAS  Google Scholar 

  87. Omuro AM, Faivre S, Raymond E (2007) Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther 6:1909–1919

    Article  CAS  Google Scholar 

  88. Collins V (2004) Brain tumours: classification and genes. J Neurol Neurosurg Psychiatry 75:ii2–ii11

    Google Scholar 

  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 11:59

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemistry, University of New South Wales, Kensington, NSW, 2052, Australia

    Jeanette McConnell, Yao Wang & Shelli McAlpine

Authors
  1. Jeanette McConnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shelli McAlpine
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shelli McAlpine .

Editor information

Editors and Affiliations

  1. School of Chemistry, University of New South Wales, Sidney, New South Wales, Australia

    Shelli R. McAlpine

  2. Biomedical Biotechnology Research Unit (BioBRU); Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa

    Adrienne Lesley Edkins

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

McConnell, J., Wang, Y., McAlpine, S. (2015). Targeting the C-Terminus of Hsp90 as a Cancer Therapy. In: McAlpine, S., Edkins, A. (eds) Heat Shock Protein Inhibitors. Topics in Medicinal Chemistry, vol 19. Springer, Cham. https://doi.org/10.1007/7355_2015_93

Download citation

Publish with us

Policies and ethics

Search

Navigation