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.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
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
Bagatell R, Whitesell L (2004) Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther 3:1021–1030
Trepel J, Mollapour M, Giaccone G et al (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537–549
Miyata Y, Nakamoto H, Neckers L (2013) The therapeutic target hsp90 and cancer hallmarks. Curr Pharm Des 19:347–365
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
Jhaveri K, Modi S (2012) HSP90 inhibitors for cancer therapy and overcoming drug resistance. Adv Pharmacol 65:471–517
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
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
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
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
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
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
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
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
Wang Y, McAlpine SR (2015) C-terminal heat shock protein 90 modulators produce desirable oncogenic properties. Org Biomol Chem 13:4627–4631
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
Wang Y, McAlpine SR (2015) Heat shock protein 90 inhibitors: will they ever succeed as chemotherapeutics? Future Med Chem 7:87–90
Wang Y, Mcalpine SR (2015) N-terminal and C-terminal modulation of Hsp90 produce dissimilar phenotypes. Chem Comm 51:1410–1413
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
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
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
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
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
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
Powers MV, Clarke PA, Workman P (2009) Death by chaperone: HSP90, HSP70 or both? Cell Cycle 8:518–526
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
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
Calderwood SK, Khaleque MA, Sawyer DB et al (2006) Heat shock proteins in cancer: chaperones of tumorigenesis. Trends Biochem Sci 31:164–172
Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124
Whitesell L, Santagata S, Lin NU (2012) Inhibiting hsp90 to treat cancer: a strategy in evolution. Curr Mol Med 12:1108–1124
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
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
Creagh EM, Sheehan D, Cotter TG (2000) Heat shock proteins–modulators of apoptosis in tumour cells. Leukemia 14:1161–1173
Beere HM (2004) “The stress of dying”: the role of heat shock proteins in the regulation of apoptosis. J Cell Sci 117:2641–2651
Takayama S, Reed JC, Homma S (2003) Heat-shock proteins as regulators of apoptosis. Oncogene 22:9041–9047
Saleh A, Srinivasula SM, Balkir L et al (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–483
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
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
Ravagnan L, Gurbuxani S, Susin SA et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843
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
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
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
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
Hsu HS, Lin JH, Huang WC et al (2011) Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27. Cancer 117:1516–1528
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
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
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
Burlison J, Blagg B (2006) Synthesis and evaluation of Coumermycin A1 analogues that inhibit the hsp90 protein machinery. Org Lett 8:4555–4558
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
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
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
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
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
Zeytuni N, Zarivach R (2012) Structural and functional discussion of the tetra-trico-peptide repeat, a protein interaction module. Structure 7:397–405
Blatch GL, Lassle M (1999) The tetratricopeptide repeat: a structural motif mediating protein-protein interactions. BioEssays 21:932–939
Caplan AJ (2003) What is a co-chaperone? Cell Stress Chaperones 8:105–107
Cortajarena AL, Yi F, Regan L (2008) Designed TPR modules as novel anticancer agents. ACS Chem Biol 3:161–166
Main ER, Xiong Y, Cocco MJ et al (2003) Design of stable alpha-helical arrays from an idealized TPR motif. Structure 11:497–508
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
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
Kabouridis PS (2003) Biological applications of protein transduction technology. Trends Biotechnol 21:498–503
Salvesen GS, Duckett CS (2002) IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol 3:401–410
Altieri DC (2003) Validating survivin as a cancer therapeutic target. Nat Rev Cancer 3:46–54
Redlak MJ, Miller TA (2011) Targeting PI3K/Akt/HSP90 signaling sensitizes gastric cancer cells to deoxycholate-induced apoptosis. Dig Dis Sci 56:323–329
Wu A, Wu B, Guo J et al (2011) Elevated expression of CDK4 in lung cancer. J Transl Med 9:38
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
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
Omuro AM, Faivre S, Raymond E (2007) Lessons learned in the development of targeted therapy for malignant gliomas. Mol Cancer Ther 6:1909–1919
Collins V (2004) Brain tumours: classification and genes. J Neurol Neurosurg Psychiatry 75:ii2–ii11
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
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights 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
DOI: https://doi.org/10.1007/7355_2015_93
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-32605-4
Online ISBN: 978-3-319-32607-8
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)