Abstract
The molecular chaperone HSP90 (heat shock protein 90) has become a crucial target in cancer therapeutics as its function has beenĀ implicated with various types of malignant transformation. Numerous HSP90 inhibitors have been identified so far and many of them have also been clinically tested. Although most of these are natural or their derived inhibitors including geldanamycin and its derivatives 17-AAG and 17-DMAGĀ have shown efficacy, their easy success has been hindered in various stages of the clinical studies due to poor solubility and cytotoxicity. However, recently substantial published documents reported that the systemic targeting of the HSP90 inhibitors using nano-based drug delivery system could provide a possible clinical solution to overcome their limitation. In this chapter, we review the initial development of various HSP90 inhibitors from natural to synthetically derived one and their clinical studies. We also review their limitations and future perspectives as a possible potential agent in the cancer therapeutics by their systemic and control delivery to the target site using the nano-drug delivery system. Also, the application of combined therapy has also been discussed in the current chapter using HSP90 inhibitors and nanocarrier. In addition, we also discuss the therapeutic approaches like photothermal where nano carrier is not only used as a carrier for the systemic delivery of HSP90 inhibitors but also as a therapeutic agent.
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Abbreviations
- 17-AAG:
-
17-allylamino-17demethoxygeldanamycin
- 17-DMAG:
-
17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin
- ADP:
-
adenosine diphosphate
- AhR:
-
aryl hydrocarbon receptor
- ATP:
-
adenosine triphosphate
- CBR:
-
clinical benefit rate
- DLT:
-
dose-limiting toxicities
- EGCG:
-
Epigallocatechin 3-gallate
- FDG-PET:
-
fluorodeoxyglucose positron emission tomography
- GIST:
-
gastrointestinal stromal tumors
- GM:
-
Geldanamycin
- HOP:
-
HSP90 organizing protein
- HSP:
-
heat shock protein
- IPI-493:
-
17-desmethoxy-17-amino Geldanamycin
- IPI-504:
-
17-allylamino-17-demethoxygeldanamycin Hydroquinone Hydro-chloride
- MDR:
-
multi-drug resistance
- MTD:
-
maximum tolerated dose
- NSCLC:
-
non-small-cell lung carcinoma
- ORR:
-
overall response rate
- PBMC:
-
peripheral blood mononuclear cells
- PCL:
-
poly(Īµ-caprolactone)
- PDGFRA:
-
platelet-derived growth factor receptor alpha
- PEG:
-
poly(ethylene glycol)
- PET:
-
positron emission tomography
- PLGA:
-
poly (lactic-co-glycolic acid)
- PR:
-
partial response
- RD:
-
radicicol
- SD:
-
stable diseases
- SUV:
-
standardized uptake value
- TNBC:
-
triple-negative breast cancer
References
Allan RK, Mok D, Ward BK, Ratajczak T (2006) Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90 evidence that coumarin antibiotics disrupt Hsp90 dimerization. J Biol Chem 281:7161ā7171
Audisio D, Messaoudi S, Cegielkowski L et al (2011) Discovery and biological activity of 6BrCaQ as an inhibitor of the Hsp90 protein folding machinery. ChemMedChem 6:804ā815
Bagatell R, Whitesell L (2004) Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther 3:1021ā1030
Bao R, Lai C-J, Wang D-G et al (2009) Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in nonāsmall cell lung cancer. Mol Cancer TherĀ 8(12): 3296ā3306
Baylon HG, Caguioa PB, Davies FE et al (2013) A phase 1/2 study of KW-2478, an Hsp 90 inhibitor, in combination with bortezomib (BTZ) in patients (Pts) with relapsed/refractory (R/R) multiple myeloma (MM). Am Soc Hematol 122: 1967
Bruni N, Stella B, Giraudo L, Della Pepa C, Gastaldi D, Dosio F (2017) Nanostructured delivery systems with improved leishmanicidal activity: a critical review. Int J Nanomedicine 12:5289
Butler LM, Ferraldeschi R, Armstrong HK, Centenera MM, Workman P (2015) Maximizing the therapeutic potential of HSP90 inhibitors. Mol Cancer Res 13:1445ā1451: molcanres. 0234.2015
Byrd KM, Subramanian C, Sanchez J etĀ al (2016) Synthesis and biological evaluation of novobiocin core analogues as Hsp90 inhibitors. Chem Eur J 22:6921ā6931
Cavenagh J, Yong K, Byrne J etĀ al (2008) The safety, pharmacokinetics and pharmacodynamics of KW-2478, a novel HSP90 antagonist, in patients with B-cell malignancies: a first-in-man, phase I, multicentre, open-label, dose escalation study. Am Soc Hematol 112(11): 2777
ChĆØne P (2002) ATPases as drug targets: learning from their structure. Nat Rev Drug Discov 1:665
Cheung K-MJ, Matthews TP, James K et al (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 15:3338ā3343
Chiosis G, Timaul MN, Lucas B et al (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 8:289ā299
Cho D, Heath E, Cleary J etĀ al (2011) A phase I dose-escalation study of the Hsp90 inhibitor ganetespib (STA-9090) administered twice weekly in patients with solid tumors: updated report. J Clin Oncol 29:3051ā3051
Demetri G, Heinrich M, Chmielowski B et al (2011) An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in patients (pts) with metastatic and/or unresectable GIST. J Clin Oncol 29:10011ā10011
Do KT, Speranza G, Chen AP et al. (2012) Phase l study assessing a two-consecutive-day (QDĆ 2) dosing schedule of the HSP90 inhibitor, AT13387, in patients with advanced solid tumors. Paper presented at the Proc Am Soc Clin Oncol
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 9:1219ā1233
Ge J, Normant E, Porter JR et al (2006) Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90. J Med Chem 49:4606ā4615
Goldman J, Raju R, Gordon G, Vukovic V, Bradley R, Rosen L (2010) A phase I dose-escalation study of the Hsp90 inhibitor STA-9090 administered once weekly in patients with solid tumors. J Clin Oncol 28:2529ā2529
Hadden MK, Galam L, Gestwicki JE, Matts RL, Blagg BS (2007) Derrubone, an inhibitor of the Hsp90 protein folding machinery. J Nat Prod 70:2014ā2018
Haque A, Alam Q, Zubair Alam M et al (2016) Current understanding of HSP90 as a novel therapeutic target: an emerging approach for the treatment of cancer. Curr Pharm Des 22:2947ā2959
He H, Zatorska D, Kim J etĀ al (2006) Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90. J Med Chem 49:381ā390
Hollingshead M, Alley M, Burger AM et al (2005) In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol 56:115ā125
Hƶlzel M, Bovier A, TĆ¼ting T (2013) Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat Rev Cancer 13:365
Isambert N, Hollebecque A, Berge Y et al (2012) A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors. Am Soc Clin OncolĀ 8(12): 3296ā3306
Jensen MR, Schoepfer J, Radimerski T et al (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10:R33
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 (BBA)-Mol Cell Res 1823:742ā755
Jhaveri K, Ochiana SO, Dunphy MP et al (2014) Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Expert Opin Investig Drugs 23:611ā628
Kasibhatla SR, Hong K, Biamonte MA et al (2007) Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity. J Med Chem 50:2767ā2778
Lamotte S, SpƤth GF, Rachidi N, Prina E (2017) The enemy within: targeting hostāparasite interaction for antileishmanial drug discovery. PLoS Negl Trop Dis 11:e0005480
Lancet JE, Smith BD, Bradley R, Komrokji RS, Teofilovici F, Rizzieri DA (2010) A phase I/II trial of the potent Hsp90 inhibitor STA-9090 administered once weekly in patients with advanced hematologic malignancies. Am Soc Hematol 116(21):3294
Li Y, Zhang T, Schwartz SJ, Sun D (2009) New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Updat 12:17ā27
Lin T-y, Guo W, Long Q et al (2016) HSP90 inhibitor encapsulated photo-theranostic nanoparticles for synergistic combination cancer therapy. Theranostics 6:1324
Mahadevan D, Rensvold DM, Kurtin SE et al (2012) First-in-human phase I study: results of a second-generation non-ansamycin heat shock protein 90 (HSP90) inhibitor AT13387 in refractory solid tumors. Am Soc Clin OncolĀ 3028
Mahalingam D, Swords R, Carew JS, Nawrocki S, Bhalla K, Giles F (2009) Targeting HSP90 for cancer therapy. Br J Cancer 100:1523
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 275:37181ā37186
Markman JL, Rekechenetskiy A, Holler E, Ljubimova JY (2013) Nanomedicine therapeutic approaches to overcome cancer drug resistance. Adv Drug Deliv Rev 65:1866ā1879
Martin CJ, Gaisser S, Challis IR et al (2008) Molecular characterization of macbecin as an Hsp90 inhibitor. J Med Chem 51:2853ā2857
Marubayashi S, Koppikar P, Taldone T et al (2010) HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. J Clin Invest 120:3578ā3593
Meacham CE, Morrison SJ (2013) Tumour heterogeneity and cancer cell plasticity. Nature 501:328
Menzella HG, Tran T-T, Carney JR et al (2009) Potent non-benzoquinone ansamycin heat shock protein 90 inhibitors from genetic engineering of Streptomyces hygroscopicus. J Med Chem 52:1518ā1521
Messaoudi S, Peyrat J, Brion J, Alami M (2008) Recent advances in Hsp90 inhibitors as antitumor agents. Anti-Cancer Agents Med Chem (Formerly Curr Med Chem-Anti-Cancer Agents) 8:761ā782
Mimnaugh EG, Chavany C, Neckers L (1996) Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J Biol Chem 271:22796ā22801
Mitchell P (2011) Biogen Idec restructures, sharpens neurology focus. Nature Biotechnology 29: 7ā8
Murray CW, Carr MG, Callaghan O et al (2010) Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency. J Med Chem 53:5942ā5955
Nakashima T, Ishii T, Tagaya H et al (2010) New molecular and biological mechanism of anti-tumor activities of KW-2478, a novel non-ansamycin Hsp90 inhibitor, in multiple myeloma cells. Clin Cancer Res 16:2792ā2802: clincanres. 3112. subyr
Neckers L (2002) Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med 8:S55āS61
Neckers L (2007) Heat shock protein 90: the cancer chaperone. In: Heat shock protein cancer. Springer, Dordrecht, pp 231ā52
Nimmanapalli R, OāBryan E, Bhalla K (2001) Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res 61:1799ā1804
Ohsuki S, Tengeiji A, Ikeda M, Shibata Y, Nagata C, Shimada T (2012) Pyrazolopyrimidine derivative: Google Patents
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 44:5041ā5052
Parveen S, Sahoo SK (2008) Polymeric nanoparticles for cancer therapy. J Drug Target 16:108ā123
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 Discovery 6:559ā587
Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271ā294
Petersen ALOA, Campos TA, Dantas DAS et al (2018) An in vitro assessment on the efficacy of a novel liposomal formulation containing the Hsp-90 inhibitor, 17-AAG. Front Cell Infect Microbiol 8:303
Proia DA, Zhang C, Sequeira M et al (2013) Preclinical activity profile and therapeutic efficacy of the HSP90 inhibitor ganetespib in triple-negative breast cancer. Clin Cancer Res: clincan resĀ 20(2):413ā424
Rochani AK, Balasubramanian S, Girija AR et al (2016) Dual mode of cancer cell destruction for pancreatic cancer therapy using Hsp90 inhibitor loaded polymeric nano magnetic formulation. Int J Pharm 511:648ā658
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 42:260ā266
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 327:176ā183
Samlowski W, Papadopoulos K, Olszanski A et al (2011) Phase 1 study of HSP90 inhibitor MPC-3100 in subjects with refractory or recurrent cancer. Mol Targets Cancer Ther 10(11): A96-A96
Samuel T, Sessa C, Britten C et al (2010) AUY922, a novel HSP90 inhibitor: final results of a first-in-human study in patients with advanced solid malignancies. J Clin Oncol 28:2528ā2528
Sauvage F, FranzĆØ S, Bruneau A et al (2016) Formulation and in vitro efficacy of liposomes containing the Hsp90 inhibitor 6BrCaQ in prostate cancer cells. Int J Pharm 499:101ā109
Schroder C, Pedersen J, Chua S et al (2011) Use of biomarkers and imaging to evaluate the treatment effect of AUY922, an HSP90 inhibitor, in patients with HER2+ or ER+ metastatic breast cancer. J Clin Oncol 29:e11024āe11e24
Shi J, Van de Water R, Hong K et al (2012) EC144 is a potent inhibitor of the heat shock protein 90. J Med Chem 55:7786ā7795
Sidera K, Patsavoudi E (2014) HSP90 inhibitors: current development and potential in cancer therapy. Recent Pat Anticancer Drug Discov 9:1ā20
Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7ā30
Soga S, Akinaga S, Shiotsu Y (2013) Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development. Curr Pharm Des 19:366ā376
Solit DB, Chiosis G (2008) Development and application of Hsp90 inhibitors. Drug Discov Today 13:38ā43
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 103:17408ā17413
Taldone T, Chiosis G (2009) Purine-scaffold Hsp90 inhibitors. Curr Top Med Chem 9:1436ā1446
Taldone T, Patel PD, Patel M et al (2013) Experimental and structural testing module to analyze paralogue-specificity and affinity in the Hsp90 inhibitors series. J Med Chem 56:6803ā6818
Tanida S, Hasegawa T, Higashide E (1980) Macbecins I and II, new antitumor antibiotics. J Antibiot 33:199ā204
Trepel J, Mollapour M, Giaccone G, Neckers L (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537
Wang J, Li Z, Lin Z et al (2015) 17-DMCHAG, a new geldanamycin derivative, inhibits prostate cancer cells through Hsp90 inhibition and survivin downregulation. Cancer Lett 362:83ā96
Won Y-W, Yoon S-M, Sonn CH, Lee K-M, Kim Y-H (2011) Nano self-assembly of recombinant human gelatin conjugated with Ī±-tocopheryl succinate for Hsp90 inhibitor, 17-AAG, delivery. ACS Nano 5:3839ā3848
Woodhead AJ, Angove H, Carr MG et al (2010) Discovery of (2, 4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1, 3-dihydroisoindol-2-yl] methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design. J Med Chem 53:5956ā5969
Xiong MP, YƔƱez JA, Remsberg CM et al (2008) Formulation of a geldanamycin prodrug in mPEG-b-PCL micelles greatly enhances tolerability and pharmacokinetics in rats. J Control Release 129:33ā40
Ying W, Du Z, Sun L et al (2011) 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
Young JC, Agashe VR, Siegers K, Hartl FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nat Rev Mol Cell Biol 5:781
Zhang H, Neely L, Lundgren K et al (2010) BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance. Int J Cancer 126:1226ā1234
Zhang X, Zhang T, Ye Y et al (2015) Phospholipid-stabilized mesoporous carbon nanospheres as versatile carriers for systemic delivery of amphiphobic SNX-2112 (a Hsp90 inhibitor) with enhanced antitumor effect. Eur J Pharm Biopharm 94:30ā41
Acknowledgements
The authors sincerely thank the Science and Engineering Research Board, Government of India, for financial support (Grant No. SERB/F/4290/2016-17) and National Institute of Technology Rourkela, Government of India, for providing the infrastructural facility for the preparation of the chapter.
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Somu, P., Paul, S. (2019). HSP90 and Its Inhibitors for Cancer Therapy: Use of Nano-delivery System to Improve Its Clinical Application. In: Asea, A., Kaur, P. (eds) Heat Shock Protein 90 in Human Diseases and Disorders. Heat Shock Proteins, vol 19. Springer, Cham. https://doi.org/10.1007/978-3-030-23158-3_8
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