Therapeutic Potential of Heat Shock Protein 90 Inhibitors, Geldanamycin, and Analog Compounds in Precision Cancer Therapy

Atta Mohammed Alzebari; Amjad Mahmood  Qadir; Mahmood Sherzad Rafaat; Abbas Salihi

doi:10.59786/bmtj.122

Authors

Atta Mohammed Alzebari Chemical Biology Group, Institute of Organic and Macro Molecular Chemistry, Friedrich Schiller University-Jena, 07737 Jena, Germany https://orcid.org/0009-0004-5668-5982
Amjad Mahmood Qadir Department of General Science, College of Basic Education, University of Halabja, 46018 Halabja, KRG, Iraq https://orcid.org/0000-0002-4142-6118
Mahmood Sherzad Rafaat Pathological Analysis Department, Paytakht Technical Institute, Erbil, 44001, Iraq https://orcid.org/0000-0002-3439-6686
Abbas Salihi Department of Biology, College of Science, Salahaddin University-Erbil, 44001, Iraq https://orcid.org/0000-0002-1342-2849

DOI:

https://doi.org/10.59786/bmtj.122

Keywords:

Cancer, Geldanamycin, Heat shock protein, Inhibitors, HSP90

Abstract

Heat shock protein (HSP90) is a molecular chaperone involved in numerous physiological processes. The primary role of this is to assist in the process of protein folding and to restore misfolded proteins to their correct shape. Chaperones additionally inhibit protein breakdown and aggregation. HSP90 inhibitors possess a notable characteristic of obstructing many cancer-causing pathways by facilitating the breakdown of numerous oncogenic client proteins. Targeting HSP90 therapeutics has been recognized as a viable approach for treating cancer and inflammatory-associated disorders in clinical studies involving different forms of cancer. Inhibition of HSP90 using natural, synthetic, and semi-synthetic chemicals has shown encouraging outcomes. HSP90 inhibitors have been extracted from several fungi, bacteria, and plant species. These naturally occurring chemicals play a crucial function in regulating HSP90 activity and can be utilized to develop innovative semi-synthetic or synthetic inhibitors. Over 120 clinical trials have been carried out to evaluate the effectiveness of HSP90 inhibitors as a supplementary therapy for different types of tumor cells. Presently, ongoing research is being carried out to acquire an understanding of innovative and more efficacious methods for treating cancer. Continuing in this research approach, we aim to investigate the discovery, biosynthesis, mechanism of action, and biological features of geldanamycin and its analogs.

Downloads

Download data is not yet available.

References

Ponomarenko M, Stepanenko I, Kolchanov N. Heat shock proteins. Brenner’s encyclopedia of genetics. 2013;3:402-405. doi:10.1016/B978-0-12-374984-0.00685-9

Chatterjee S, Burns TF. Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach. Int J Mol Sci. Sep 15 2017;18(9):1978. doi:10.3390/ijms18091978

McConnell JR, McAlpine SR. Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorganic & medicinal chemistry letters. 2013;23(7):1923-1928.

Maloney A, Workman P. HSP90 as a new therapeutic target for cancer therapy: the story unfolds. Expert Opin Biol Ther. Jan 2002;2(1):3-24. doi:10.1517/14712598.2.1.3

Sarto C, Binz PA, Mocarelli P. Heat shock proteins in human cancer. Electrophoresis. Apr 2000;21(6):1218-26. doi:10.1002/(SICI)1522-2683(20000401)21:6<1218::AID-ELPS1218>3.0.CO;2-H

Harrison SE, Sozen B, Christodoulou N, Kyprianou C, Zernicka-Goetz M. Assembly of embryonic and extraembryonic stem cells to mimic embryogenesis in vitro. Science. Apr 14 2017;356(6334):eaal1810. doi:10.1126/science.aal1810

Hipp MS, Kasturi P, Hartl FU. The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol. Jul 2019;20(7):421-435. doi:10.1038/s41580-019-0101-y

Kostenko S, Moens U. Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology. Cell Mol Life Sci. Oct 2009;66(20):3289-307. doi:10.1007/s00018-009-0086-3

Bose S, Cho J. Targeting chaperones, heat shock factor-1, and unfolded protein response: Promising therapeutic approaches for neurodegenerative disorders. Ageing Res Rev. May 2017;35:155-175. doi:10.1016/j.arr.2016.09.004

Alberti G, Paladino L, Vitale AM, et al. Functions and Therapeutic Potential of Extracellular Hsp60, Hsp70, and Hsp90 in Neuroinflammatory Disorders. Applied Sciences. 2021;11(2):736.

Malyshev I. Immunity, tumors and aging: the role of Hsp70. Springer Science & Business Media; 2013.

Haque A, Alam Q, Zubair Alam M, et al. Current understanding of HSP90 as a novel therapeutic target: an emerging approach for the treatment of cancer. Current pharmaceutical design. 2016;22(20):2947-2959.

Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C. Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med. Jun 2008;12(3):743-61. doi:10.1111/j.1582-4934.2008.00273.x

Rauch JN, Tse E, Freilich R, et al. BAG3 is a modular, scaffolding protein that physically links heat shock protein 70 (Hsp70) to the small heat shock proteins. Journal of molecular biology. 2017;429(1):128-141.

Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C. Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol. Jan 2007;81(1):15-27. doi:10.1189/jlb.0306167

Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat Shock Proteins and Cancer. Trends Pharmacol Sci. Mar 2017;38(3):226-256. doi:10.1016/j.tips.2016.11.009

Wang X, Chen M, Zhou J, Zhang X. HSP27, 70 and 90, anti-apoptotic proteins, in clinical cancer therapy (Review). Int J Oncol. Jul 2014;45(1):18-30. doi:10.3892/ijo.2014.2399

Hoppe-Seyler F, Crnkovic-Mertens I, Tomai E, Butz K. Peptide aptamers: specific inhibitors of protein function. Curr Mol Med. Aug 2004;4(5):529-38. doi:10.2174/1566524043360519

Rocchi P, Jugpal P, So A, et al. Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via caspase-3 activation in vitro. BJU Int. Nov 2006;98(5):1082-9. doi:10.1111/j.1464-410X.2006.06425.x

Batulan Z, Pulakazhi Venu VK, Li Y, et al. Extracellular Release and Signaling by Heat Shock Protein 27: Role in Modifying Vascular Inflammation. Front Immunol. 2016;7:285. doi:10.3389/fimmu.2016.00285

Li J, Qian X, Sha B. Heat shock protein 40: structural studies and their functional implications. Protein and peptide letters. 2009;16(6):606-612.

Chen T, Lin T, Li H, et al. Heat Shock Protein 40 (HSP40) in Pacific White Shrimp (Litopenaeus vannamei): Molecular Cloning, Tissue Distribution and Ontogeny, Response to Temperature, Acidity/Alkalinity and Salinity Stresses, and Potential Role in Ovarian Development. Front Physiol. 2018;9:1784. doi:10.3389/fphys.2018.01784

Young JC. Mechanisms of the Hsp70 chaperone system. Biochem Cell Biol. Apr 2010;88(2):291-300. doi:10.1139/o09-175

Shonhai A, Maier AG, Przyborski JM, Blatch GL. Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. Protein Pept Lett. Feb 2011;18(2):143-57. doi:10.2174/092986611794475002

Iyer K, Chand K, Mitra A, Trivedi J, Mitra D. Diversity in heat shock protein families: functional implications in virus infection with a comprehensive insight of their role in the HIV-1 life cycle. Cell Stress and Chaperones. 2021;26:743-768.

Lianos GD, Alexiou GA, Mangano A, et al. The role of heat shock proteins in cancer. Cancer Lett. May 1 2015;360(2):114-8. doi:10.1016/j.canlet.2015.02.026

Bottoni P, Giardina B, Scatena R. Proteomic profiling of heat shock proteins: An emerging molecular approach with direct pathophysiological and clinical implications. Proteomics Clin Appl. Jun 2009;3(6):636-53. doi:10.1002/prca.200800195

Duan Y, Tang H, Mitchell-Silbaugh K, Fang X, Han Z, Ouyang K. Heat Shock Protein 60 in Cardiovascular Physiology and Diseases. Front Mol Biosci. 2020;7:73. doi:10.3389/fmolb.2020.00073

Krishnan-Sivadoss I, Mijares-Rojas IA, Villarreal-Leal RA, Torre-Amione G, Knowlton AA, Guerrero-Beltran CE. Heat shock protein 60 and cardiovascular diseases: An intricate love-hate story. Med Res Rev. Jan 2021;41(1):29-71. doi:10.1002/med.21723

Xanthoudakis S, Roy S, Rasper D, et al. Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. The EMBO journal. Apr 15 1999;18(8):2049-56. doi:10.1093/emboj/18.8.2049

Javid H, Hashemian P, Yazdani S, Sharbaf Mashhad A, Karimi-Shahri M. The role of heat shock proteins in metastatic colorectal cancer: A review. J Cell Biochem. Nov 2022;123(11):1704-1735. doi:10.1002/jcb.30326

Gottesman S, Wickner S, Maurizi MR. Protein quality control: triage by chaperones and proteases. Genes Dev. Apr 1 1997;11(7):815-23. doi:10.1101/gad.11.7.815

Sun B, Li G, Yu Q, Liu D, Tang X. HSP60 in cancer: a promising biomarker for diagnosis and a potentially useful target for treatment. J Drug Target. Jan 2022;30(1):31-45. doi:10.1080/1061186X.2021.1920025

Kiang JG, Tsokos GC. Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacol Ther. Nov 1998;80(2):183-201. doi:10.1016/s0163-7258(98)00028-x

Evans CG, Chang L, Gestwicki JE. Heat shock protein 70 (hsp70) as an emerging drug target. Journal of medicinal chemistry. 2010;53(12):4585-4602.

Hartl FU, Martin J, Neupert W. Protein folding in the cell: the role of molecular chaperones Hsp70 and Hsp60. Annu Rev Biophys Biomol Struct. 1992;21(1):293-322. doi:10.1146/annurev.bb.21.060192.001453

Calderwood SK, Mambula SS, Gray PJ, Jr. Extracellular heat shock proteins in cell signaling and immunity. Ann N Y Acad Sci. Oct 2007;1113(1):28-39. doi:10.1196/annals.1391.019

Isabelle M, Moreel X, Gagne JP, et al. Investigation of PARP-1, PARP-2, and PARG interactomes by affinity-purification mass spectrometry. Proteome Sci. Apr 13 2010;8(1):22. doi:10.1186/1477-5956-8-22

Garg G, Khandelwal A, Blagg BS. Anticancer Inhibitors of Hsp90 Function: Beyond the Usual Suspects. Adv Cancer Res. 2016;129:51-88. doi:10.1016/bs.acr.2015.12.001

Lee CC, Lin TW, Ko TP, Wang AH. The hexameric structures of human heat shock protein 90. PLoS One. 2011;6(5):e19961. doi:10.1371/journal.pone.0019961

Messaoudi S, Peyrat JF, Brion JD, Alami M. Recent advances in Hsp90 inhibitors as antitumor agents. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents). 2008;8(7):761-782.

Audisio D, Messaoudi S, Ijjaali I, et al. Assessing the chemical diversity of an hsp90 database. Eur J Med Chem. May 2010;45(5):2000-9. doi:10.1016/j.ejmech.2010.01.048

Prevarskaya N, Skryma R, Shuba Y. Ion channels and the hallmarks of cancer. Trends Mol Med. Mar 2010;16(3):107-21. doi:10.1016/j.molmed.2010.01.005

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

Supko JG, Hickman RL, Grever MR, Malspeis L. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer chemotherapy and pharmacology. 1995;36:305-315.

Gartner EM, Silverman P, Simon M, et al. A phase II study of 17-allylamino-17-demethoxygeldanamycin in metastatic or locally advanced, unresectable breast cancer. Breast Cancer Res Treat. Feb 2012;131(3):933-7. doi:10.1007/s10549-011-1866-7

Soga S, Shiotsu Y, Akinaga S, Sharma SV. Development of radicicol analogues. Curr Cancer Drug Targets. Oct 2003;3(5):359-69. doi:10.2174/1568009033481859

Skrzypczak N, Pyta K, Ruszkowski P, Gdaniec M, Bartl F, Przybylski P. Synthesis, structure and anticancer activity of new geldanamycin amine analogs containing C (17)-or C (20)-flexible and rigid arms as well as closed or open ansa-bridges. European Journal of Medicinal Chemistry. 2020;202:112624.

Chatterjee S, Burns TF. Targeting heat shock proteins in cancer: a promising therapeutic approach. International journal of molecular sciences. 2017;18(9):1978.

Solárová Z, MOJžiš J, SOLáR P. Hsp90 inhibitor as a sensitizer of cancer cells to different therapies. International Journal of Oncology. 2015;46(3):907-926.

Moser C, Lang SA, Stoeltzing O. Heat-shock protein 90 (Hsp90) as a molecular target for therapy of gastrointestinal cancer. Anticancer research. 2009;29(6):2031-2042.

Mahalingam D, Swords R, Carew JS, Nawrocki ST, Bhalla K, Giles FJ. Targeting HSP90 for cancer therapy. Br J Cancer. May 19 2009;100(10):1523-9. doi:10.1038/sj.bjc.6605066

Li L, Wang L, You QD, Xu XL. Heat Shock Protein 90 Inhibitors: An Update on Achievements, Challenges, and Future Directions. J Med Chem. Mar 12 2020;63(5):1798-1822. doi:10.1021/acs.jmedchem.9b00940

Zuehlke AD, Moses MA, Neckers L. Heat shock protein 90: its inhibition and function. Philos Trans R Soc Lond B Biol Sci. Jan 19 2018;373(1738):20160527. doi:10.1098/rstb.2016.0527

Schulte TW, Neckers LM. The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol. 1998;42(4):273-9. doi:10.1007/s002800050817

Costa T, Raghavendra NM, Penido C. Natural heat shock protein 90 inhibitors in cancer and inflammation. Eur J Med Chem. Mar 1 2020;189:112063. doi:10.1016/j.ejmech.2020.112063

Banerjee M, Hatial I, Keegan BM, Blagg BS. Assay design and development strategies for finding Hsp90 inhibitors and their role in human diseases. Pharmacology & therapeutics. 2021;221:107747.

Garcia-Carbonero R, Carnero A, Paz-Ares L. Inhibition of HSP90 molecular chaperones: moving into the clinic. The Lancet Oncology. 2013;14(9):e358-e369.

Lu R-C, Tan M-S, Wang H, Xie A-M, Yu J-T, Tan L. Heat shock protein 70 in Alzheimer’s disease. BioMed research international. 2014;2014

He W, Hu H. BIIB021, an Hsp90 inhibitor: A promising therapeutic strategy for blood malignancies (Review). Oncol Rep. Jul 2018;40(1):3-15. doi:10.3892/or.2018.6422

Workman P, Burrows F, Neckers L, Rosen N. Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci. Oct 2007;1113(1):202-16. doi:10.1196/annals.1391.012

Miyata Y, Nakamoto H, Neckers L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des. 2013;19(3):347-65. doi:10.2174/138161213804143725

Usmani SZ, Bona R, Li Z. 17 AAG for HSP90 inhibition in cancer--from bench to bedside. Curr Mol Med. Jun 2009;9(5):654-64. doi:10.2174/156652409788488757

Wang C, Zhang Y, Guo K, et al. Heat shock proteins in hepatocellular carcinoma: Molecular mechanism and therapeutic potential. Int J Cancer. Apr 15 2016;138(8):1824-34. doi:10.1002/ijc.29723

Proia DA, Kaufmann GF. Targeting heat-shock protein 90 (HSP90) as a complementary strategy to immune checkpoint blockade for cancer therapy. Cancer immunology research. 2015;3(6):583-589.

Banerji U, O'Donnell A, Scurr M, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol. Jun 20 2005;23(18):4152-61. doi:10.1200/JCO.2005.00.612

Jhaveri K, Ochiana SO, Dunphy MP, et al. Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Expert Opin Investig Drugs. May 2014;23(5):611-28. doi:10.1517/13543784.2014.902442

Kryeziu K, Bruun J, Guren TK, Sveen A, Lothe RA. Combination therapies with HSP90 inhibitors against colorectal cancer. Biochim Biophys Acta Rev Cancer. Apr 2019;1871(2):240-247. doi:10.1016/j.bbcan.2019.01.002

Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: are we there yet? Clinical cancer research. 2012;18(1):64-76.

Fuhrmann-Stroissnigg H, Niedernhofer LJ, Robbins PD. Hsp90 inhibitors as senolytic drugs to extend healthy aging. Cell Cycle. 2018;17(9):1048-1055.

Aherne W, Maloney A, Prodromou C, et al. Assays for HSP90 and inhibitors. Methods Mol Med. 2003;85:149-61. doi:10.1385/1-59259-380-1:149

Skrzypczak N, Przybylski P. Modifications, biological origin and antibacterial activity of naphthalenoid ansamycins. Nat Prod Rep. Sep 21 2022;39(9):1653-1677. doi:10.1039/d2np00002d

Skrzypczak N, Przybylski P. Structural diversity and biological relevance of benzenoid and atypical ansamycins and their congeners. Natural Product Reports. 2022;39(9):1678-1704.

Hager A. Studies towards total synthesis of polyketide natural products and alkaloids. lmu; 2012.

Funayama S, Cordell GA. Ansamycin antibioticsA discovery, classification, biosynthesis and biological activities. Studies in Natural Products Chemistry. 2000;23:51-106.

Wang J, Li Z, Lin Z, et al. 17-DMCHAG, a new geldanamycin derivative, inhibits prostate cancer cells through Hsp90 inhibition and survivin downregulation. Cancer Letters. 2015;362(1):83-96.

Park JW, Yeh MW, Wong MG, et al. The heat shock protein 90-binding geldanamycin inhibits cancer cell proliferation, down-regulates oncoproteins, and inhibits epidermal growth factor-induced invasion in thyroid cancer cell lines. J Clin Endocrinol Metab. Jul 2003;88(7):3346-53. doi:10.1210/jc.2002-020340

Kim C-G, Kirschning A, Bergon P, et al. Biosynthesis of 3-amino-5-hydroxybenzoic acid, the precursor of mC7N units in ansamycin antibiotics. Journal of the American Chemical Society. 1996;118(32):7486-7491.

Hassall C, Magnus K. Monamycin: a new antibiotic. Nature. 1959;184(4694):1223-1224.

Kitson RR, Moody CJ. Synthesis of novel geldanamycin derivatives. Tetrahedron. 2021;82:131927.

Martín JF, Ramos A, Liras P. Regulation of geldanamycin biosynthesis by cluster-situated transcription factors and the master regulator PhoP. Antibiotics. 2019;8(3):87.

Hermane J, Eichner S, Mancuso L, et al. New geldanamycin derivatives with anti Hsp properties by mutasynthesis. Org Biomol Chem. May 29 2019;17(21):5269-5278. doi:10.1039/c9ob00892f

Patel K, Piagentini M, Rascher A, et al. Engineered biosynthesis of geldanamycin analogs for Hsp90 inhibition. Chem Biol. Dec 2004;11(12):1625-33. doi:10.1016/j.chembiol.2004.09.012

Rascher A, Hu Z, Buchanan GO, Reid R, Hutchinson CR. Insights into the biosynthesis of the benzoquinone ansamycins geldanamycin and herbimycin, obtained by gene sequencing and disruption. Applied and environmental microbiology. 2005;71(8):4862-4871.

Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM. 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. Aug 30 1994;91(18):8324-8. doi:10.1073/pnas.91.18.8324

Mellatyar H, Talaei S, Pilehvar-Soltanahmadi Y, et al. Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art. Biomedicine & Pharmacotherapy. 2018;102:608-617.

Kummar S, Gutierrez ME, Gardner ER, et al. Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur J Cancer. Jan 2010;46(2):340-7. doi:10.1016/j.ejca.2009.10.026

Lancet JE, Gojo I, Burton M, et al. 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. Apr 2010;24(4):699-705. doi:10.1038/leu.2009.292

Song D, Chaerkady R, Tan AC, et al. Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer. Mol Cancer Ther. Oct 2008;7(10):3275-84. doi:10.1158/1535-7163.MCT-08-0508

Jang WJ, Jung SK, Kang JS, et al. Anti‐tumor activity of WK 88‐1, a novel geldanamycin derivative, in gefitinib‐resistant non‐small cell lung cancers with Met amplification. Cancer science. 2014;105(10):1245-1253.

Skrzypczak N, Pyta K, Ruszkowski P, et al. Anticancer activity and toxicity of new quaternary ammonium geldanamycin derivative salts and their mixtures with potentiators. Journal of Enzyme Inhibition and Medicinal Chemistry. 2021;36(1):1898-1904.

Ali AA. 1, 2, 3-Triazoles: Synthesis and biological application. IntechOpen; 2020.

Magwenyane AM, Ugbaja SC, Amoako DG, Somboro AM, Khan RB, Kumalo HM. Heat shock protein 90 (HSP90) inhibitors as anticancer medicines: a review on the computer-aided drug discovery approaches over the past five years. Computational and mathematical methods in medicine. 2022;2022

Ghadban T, Jessen A, Reeh M, et al. In vitro study comparing the efficacy of the water-soluble HSP90 inhibitors, 17-AEPGA and 17-DMAG, with that of the non‑water-soluble HSP90 inhibitor, 17-AAG, in breast cancer cell lines. International Journal of Molecular Medicine. 2016;38(4):1296-1302.

Kabakov AE, Kudryavtsev VA, Gabai VL. Hsp90 inhibitors as promising agents for radiotherapy. Journal of molecular medicine. 2010;88:241-247.

Sydor JR, Normant E, Pien CS, et al. Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci U S A. Nov 14 2006;103(46):17408-13. doi:10.1073/pnas.0608372103

Moradi Z, Mohammadian M, Saberi H, et al. Anti-cancer effects of chemotherapeutic agent; 17-AAG, in combined with gold nanoparticles and irradiation in human colorectal cancer cells. Daru. Jun 2019;27(1):111-119. doi:10.1007/s40199-019-00251-w

Bagatell R, Whitesell L. Altered Hsp90 function in cancer: a unique therapeutic opportunity. Mol Cancer Ther. Aug 2004;3(8):1021-30.

Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood). Feb 2003;228(2):111-33. doi:10.1177/153537020322800201

Giménez Ortiz A, Montalar Salcedo J. Heat shock proteins as targets in oncology. Clinical and Translational Oncology. 2010;12:166-173.

Biamonte MA, Van de Water R, Arndt JW, Scannevin RH, Perret D, Lee WC. Heat shock protein 90: inhibitors in clinical trials. J Med Chem. Jan 14 2010;53(1):3-17. doi:10.1021/jm9004708

Burris HA, 3rd, Berman D, Murthy B, Jones S. Tanespimycin pharmacokinetics: a randomized dose-escalation crossover phase 1 study of two formulations. Cancer Chemother Pharmacol. May 2011;67(5):1045-54. doi:10.1007/s00280-010-1398-6

Pradhan R, Poudel BK, Choi JY, et al. Preparation and evaluation of 17-allyamino-17-demethoxygeldanamycin (17-AAG)-loaded poly (lactic acid-co-glycolic acid) nanoparticles. Archives of pharmacal research. 2015;38:734-741.

Kosova F, Kasar Z, Tuglu I, et al. Apoptosis of colon cancer cells under the effect of geldanamycin derivate. Bratisl Lek Listy. 2017;118(5):288-291. doi:10.4149/BLL_2017_058

Pacey S, Gore M, Chao D, et al. A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest New Drugs. Feb 2012;30(1):341-9. doi:10.1007/s10637-010-9493-4

Zuo Y, Xu H, Chen Z, et al. 17‑AAG synergizes with Belinostat to exhibit a negative effect on the proliferation and invasion of MDA‑MB‑231 breast cancer cells. Oncol Rep. Jun 2020;43(6):1928-1944. doi:10.3892/or.2020.7563

Ebrahimpour M, Mohammadian M, Pourheydar B, Moradi Z, Behrouzkia Z. Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells. J Lasers Med Sci. 2022;13:e9. doi:10.34172/jlms.2022.09

Pires VC, Magalhães CP, Ferrante M, et al. Solid lipid nanoparticles as a novel formulation approach for tanespimycin (17-AAG) against leishmania infections: Preparation, characterization and macrophage uptake. Acta Tropica. 2020;211:105595.

Li H-M, Li B, Sun X, et al. Enzymatic biosynthesis and biological evaluation of novel 17-AAG glucoside as potential anti-cancer agents. Bioorganic & Medicinal Chemistry Letters. 2020;30(15):127282.

Leng AM, Liu T, Yang J, et al. The apoptotic effect and associated signalling of HSP90 inhibitor 17-DMAG in hepatocellular carcinoma cells. Cell Biol Int. Oct 1 2012;36(10):893-9. doi:10.1042/CBI20110473

Zhang J, Wang K, Qi J, Cao X, Wang F. The Hsp90 Inhibitor 17-DMAG Attenuates Hyperglycemia-Enhanced Hemorrhagic Transformation in Experimental Stroke. Biomed Res Int. 2021;2021:6668442. doi:10.1155/2021/6668442

Guswanto A, Nugraha AB, Tuvshintulga B, et al. 17-DMAG inhibits the multiplication of several Babesia species and Theileria equi on in vitro cultures, and Babesia microti in mice. International Journal for Parasitology: Drugs and Drug Resistance. 2018;8(1):104-111.

Tsai YC, Leu SY, Chen SY, et al. 17-DMAG, an Hsp90 inhibitor, ameliorates ovariectomy-induced obesity in rats. Life Sci. Sep 1 2019;232:116672. doi:10.1016/j.lfs.2019.116672

Smith V, Sausville EA, Camalier RF, Fiebig HH, Burger AM. Comparison of 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17DMAG) and 17-allylamino-17-demethoxygeldanamycin (17AAG) in vitro: effects on Hsp90 and client proteins in melanoma models. Cancer Chemother Pharmacol. Aug 2005;56(2):126-37. doi:10.1007/s00280-004-0947-2

Moreno-Farre J, Asad Y, Pacey S, Workman P, Raynaud FI. Development and validation of a liquid chromatography/tandem mass spectrometry method for the determination of the novel anticancer agent 17-DMAG in human plasma. Rapid Commun Mass Spectrom. 2006;20(19):2845-50. doi:10.1002/rcm.2668

Jez JM, Chen JC, Rastelli G, Stroud RM, Santi DV. Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem Biol. Apr 2003;10(4):361-8. doi:10.1016/s1074-5521(03)00075-9

Fukumoto R, Kiang JG. Geldanamycin analog 17-DMAG limits apoptosis in human peripheral blood cells by inhibition of p53 activation and its interaction with heat-shock protein 90 kDa after exposure to ionizing radiation. Radiat Res. Sep 2011;176(3):333-45. doi:10.1667/rr2534.1

Egorin MJ, Lagattuta TF, Hamburger DR, et al. Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD 2 F 1 mice and Fischer 344 rats. Cancer chemotherapy and pharmacology. 2002;49:7-19.

Eiseman JL, Lan J, Lagattuta TF, et al. Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino) ethyl] amino] geldanamycin (17DMAG, NSC 707545) in CB-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts. Cancer chemotherapy and pharmacology. 2005;55:21-32.

Glaze ER, Lambert AL, Smith AC, et al. Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance. Cancer chemotherapy and pharmacology. 2005;56:637-647.

Smith MA, Morton CL, Phelps DA, et al. Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program. Pediatr Blood Cancer. Jul 2008;51(1):34-41. doi:10.1002/pbc.21508

Neckers L. Heat shock protein 90: the cancer chaperone. J Biosci. Apr 2007;32(3):517-30. doi:10.1007/s12038-007-0051-y

Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH. Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell. Jul 11 1997;90(1):65-75. doi:10.1016/s0092-8674(00)80314-1

Ayrault O, Godeny MD, Dillon C, et al. Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma. Proc Natl Acad Sci U S A. Oct 6 2009;106(40):17037-42. doi:10.1073/pnas.0902880106

Ramanathan RK, Egorin MJ, Erlichman C, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors. J Clin Oncol. Mar 20 2010;28(9):1520-6. doi:10.1200/JCO.2009.25.0415

Pacey S, Wilson RH, Walton M, et al. 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. Mar 15 2011;17(6):1561-70. doi:10.1158/1078-0432.CCR-10-1927

Jhaveri K, Miller K, Rosen L, et al. A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS-1022; 17 DMAG) in the treatment of advanced solid tumors. Clin Cancer Res. Sep 15 2012;18(18):5090-8. doi:10.1158/1078-0432.CCR-11-3200

Sequist LV, Gettinger S, Senzer NN, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non–small-cell lung cancer. Journal of clinical oncology. 2010;28(33):4953.

Oh WK, Galsky MD, Stadler WM, et al. Multicenter Phase 2 trial of the Hsp-90 Inhibitor, IPI-504 (retaspimycin hydrochloride), in patients with castration-resistant prostate cancer. Urology. 2011;78(3):626.

Hwang M, Moretti L, Lu B. HSP90 inhibitors: multi-targeted antitumor effects and novel combinatorial therapeutic approaches in cancer therapy. Curr Med Chem. 2009;16(24):3081-92. doi:10.2174/092986709788802999

Wagner AJ, Chugh R, Rosen LS, et al. A phase I study of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft-tissue sarcomas. Clin Cancer Res. Nov 1 2013;19(21):6020-9. doi:10.1158/1078-0432.CCR-13-0953

Patterson J, Palombella VJ, Fritz C, Normant E. IPI-504, a novel and soluble HSP-90 inhibitor, blocks the unfolded protein response in multiple myeloma cells. Cancer Chemother Pharmacol. May 2008;61(6):923-32. doi:10.1007/s00280-007-0546-0

Floris G, Debiec-Rychter M, Wozniak A, et al. 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. Oct 2011;10(10):1897-908. doi:10.1158/1535-7163.MCT-11-0148

Scaltriti M, Serra V, Normant E, et al. Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer. Mol Cancer Ther. May 2011;10(5):817-24. doi:10.1158/1535-7163.MCT-10-0966

Normant E, Paez G, West K, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4–ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene. 2011;30(22):2581-2586.

Gorska M, Popowska U, Sielicka-Dudzin A, et al. Geldanamycin and its derivatives as Hsp90 inhibitors. Frontiers in Bioscience-Landmark. 2012;17(6):2269-2277.

Leow CC, Chesebrough J, Coffman KT, et al. Antitumor efficacy of IPI-504, a selective heat shock protein 90 inhibitor against human epidermal growth factor receptor 2–positive human xenograft models as a single agent and in combination with trastuzumab or lapatinib. Molecular cancer therapeutics. 2009;8(8):2131-2141.

Di K, Keir ST, Alexandru-Abrams D, et al. Profiling Hsp90 differential expression and the molecular effects of the Hsp90 inhibitor IPI-504 in high-grade glioma models. J Neurooncol. Dec 2014;120(3):473-81. doi:10.1007/s11060-014-1579-y

Kim YS, Alarcon SV, Lee S, et al. Update on Hsp90 inhibitors in clinical trial. Curr Top Med Chem. 2009;9(15):1479-92. doi:10.2174/156802609789895728

Floris G, Sciot R, Wozniak A, et al. The Novel HSP90 inhibitor, IPI-493, is highly effective in human gastrostrointestinal stromal tumor xenografts carrying heterogeneous KIT mutations. Clinical Cancer Research. 2011;17(17):5604-5614.

Mielczarek-Lewandowska A, Hartman ML, Czyz M. Inhibitors of HSP90 in melanoma. Apoptosis. Feb 2020;25(1-2):12-28. doi:10.1007/s10495-019-01577-1

Kurop MK, Huyen CM, Kelly JH, Blagg BSJ. The heat shock response and small molecule regulators. Eur J Med Chem. Dec 15 2021;226:113846. doi:10.1016/j.ejmech.2021.113846

Sidera K, Patsavoudi E. HSP90 inhibitors: current development and potential in cancer therapy. Recent Pat Anticancer Drug Discov. Jan 2014;9(1):1-20.

Soga S, Akinaga S, Shiotsu Y. Hsp90 inhibitors as anti-cancer agents, from basic discoveries to clinical development. Current pharmaceutical design. 2013;19(3):366-376.