Recent Advances in the Discovery of Novel HSP90 Inhibitors: An Update from 2014

Author(s): Yan Xiao, Yajun Liu*.

Journal Name: Current Drug Targets

Volume 21 , Issue 3 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

HSP90 is a member of the family of heat shock proteins responsible for folding proteins into mature conformations and thus maintaining their biological function in cells. Since it is involved in all hallmarks of cancer, HSP90 has been considered as a promising drug target for cancer therapy. Eighteen HSP90 inhibitors have entered clinical trials, however, none has been approved by the FDA. There is still a great need for novel HSP90 inhibitors with strong anticancer activity and good safety profile. In the past several years, many new molecules were identified as HSP90 inhibitors and some of them have shown promising pharmacological profiles in preclinical evaluations. In this review, HSP90 inhibitors identified from 2014 to date are summarized and their design strategies, chemical structures, and biological activities are reviewed. The inhibitors are categorized by their different target domains and selectivity as N-terminal, C-terminal, and isoform-selective HSP90 inhibitors.

Keywords: HSP90, anticancer, drug design, HSP90 inhibitor, HSP90β, GRP94, lead optimization.

[1]
Lindquist S, Craig EA. The heat-shock proteins. Annu Rev Genet 1988; 22: 631-77.
[http://dx.doi.org/10.1146/annurev.ge.22.120188.003215] [PMID: 2853609]
[2]
Kim YE, Hipp MS, Bracher A, Hayer-Hartl M, Hartl FU. Molecular chaperone functions in protein folding and proteostasis. Annu Rev Biochem 2013; 82: 323-55.
[http://dx.doi.org/10.1146/annurev-biochem-060208-092442] [PMID: 23746257]
[3]
Craig EA, Gambill BD, Nelson RJ. Heat shock proteins: molecular chaperones of protein biogenesis. Microbiol Rev 1993; 57(2): 402-14.
[PMID: 8336673]
[4]
Picard D. Heat-shock protein 90, a chaperone for folding and regulation. Cell Mol Life Sci 2002; 59(10): 1640-8.
[http://dx.doi.org/10.1007/PL00012491] [PMID: 12475174]
[5]
Hoter A, El-Sabban ME, Naim HY. The HSP90 Family: Structure, regulation, function, and implications in health and disease. Int J Mol Sci 2018; 19(9)E2560
[http://dx.doi.org/10.3390/ijms19092560] [PMID: 30158430]
[6]
Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol 2017; 18(6): 345-60.
[http://dx.doi.org/10.1038/nrm.2017.20] [PMID: 28429788]
[7]
An WG, Schulte TW, Neckers LM. The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210bcr-abl and v-src proteins before their degradation by the proteasome. Cell Growth Differ 2000; 11(7): 355-60.
[PMID: 10939589]
[8]
Mimnaugh EG, Chavany C, Neckers L. Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J Biol Chem 1996; 271(37): 22796-801.
[http://dx.doi.org/10.1074/jbc.271.37.22796] [PMID: 8798456]
[9]
Pearl LH, Prodromou C. Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 2006; 75: 271-94.
[http://dx.doi.org/10.1146/annurev.biochem.75.103004.142738] [PMID: 16756493]
[10]
Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S. Heat Shock Proteins and Cancer. Trends Pharmacol Sci 2017; 38(3): 226-56.
[http://dx.doi.org/10.1016/j.tips.2016.11.009] [PMID: 28012700]
[11]
Lianos GD, Alexiou GA, Mangano A, et al. The role of heat shock proteins in cancer. Cancer Lett 2015; 360(2): 114-8.
[http://dx.doi.org/10.1016/j.canlet.2015.02.026] [PMID: 25721081]
[12]
Kaigorodova EV, Bogatyuk MV. Heat shock proteins as prognostic markers of cancer. Curr Cancer Drug Targets 2014; 14(8): 713-26.
[http://dx.doi.org/10.2174/1568009614666140926122846] [PMID: 25258164]
[13]
Khalil AA, Kabapy NF, Deraz SF, Smith C. Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets? Biochim Biophys Acta 2011; 1816(2): 89-104.
[PMID: 21605630]
[14]
Miyata Y, Nakamoto H, Neckers L. The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des 2013; 19(3): 347-65.
[http://dx.doi.org/10.2174/138161213804143725] [PMID: 22920906]
[15]
Neckers L. Heat shock protein 90: the cancer chaperone. J Biosci 2007; 32(3): 517-30.
[http://dx.doi.org/10.1007/s12038-007-0051-y] [PMID: 17536171]
[16]
Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 2003; 425(6956): 407-10.
[http://dx.doi.org/10.1038/nature01913] [PMID: 14508491]
[17]
Lackie RE, Maciejewski A, Ostapchenko VG, et al. The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases. Front Neurosci 2017; 11: 254.
[http://dx.doi.org/10.3389/fnins.2017.00254] [PMID: 28559789]
[18]
Campanella C, Pace A, Caruso Bavisotto C, et al. Heat shock proteins in alzheimer’s disease: role and targeting. Int J Mol Sci 2018; 19(9): 2603.
[http://dx.doi.org/10.3390/ijms19092603] [PMID: 30200516]
[19]
Wang X, Venable J, LaPointe P, et al. Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 2006; 127(4): 803-15.
[http://dx.doi.org/10.1016/j.cell.2006.09.043] [PMID: 17110338]
[20]
Wang Y, Jin F, Wang R, et al. HSP90: a promising broad-spectrum antiviral drug target. Arch Virol 2017; 162(11): 3269-82.
[http://dx.doi.org/10.1007/s00705-017-3511-1] [PMID: 28780632]
[21]
Cowen LE, Singh SD, Köhler JR, et al. Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease. Proc Natl Acad Sci USA 2009; 106(8): 2818-23.
[http://dx.doi.org/10.1073/pnas.0813394106] [PMID: 19196973]
[22]
Lamoth F, Juvvadi PR, Steinbach WJ. Heat shock protein 90 (Hsp90): A novel antifungal target against Aspergillus fumigatus. Crit Rev Microbiol 2016; 42(2): 310-21.
[PMID: 25243616]
[23]
Devaney E, Gillan V. Hsp90 Inhibitors in Parasitic Nematodes: Prospects and Challenges. Curr Top Med Chem 2016; 16(25): 2805-11.
[http://dx.doi.org/10.2174/1568026616666160413140502] [PMID: 27072703]
[24]
Wang K, Shang Y, Dou F. Brain Aging: Hsp90 and Neurodegenerative Diseases. Adv Exp Med Biol 2018; 1086: 93-103.
[http://dx.doi.org/10.1007/978-981-13-1117-8_6] [PMID: 30232754]
[25]
Fuhrmann-Stroissnigg H, Ling YY, Zhao J, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 2017; 8(1): 422.
[http://dx.doi.org/10.1038/s41467-017-00314-z] [PMID: 28871086]
[26]
Janssens GE, Lin XX, Millan-Ariño L, et al. Transcriptomics-based screening identifies pharmacological inhibition of hsp90 as a means to defer aging. Cell Rep 2019; 27(2): 467-480.e6.
[http://dx.doi.org/10.1016/j.celrep.2019.03.044] [PMID: 30970250]
[27]
Nahleh Z, Tfayli A, Najm A, El Sayed A, Nahle Z. Heat shock proteins in cancer: targeting the ‘chaperones’. Future Med Chem 2012; 4(7): 927-35.
[http://dx.doi.org/10.4155/fmc.12.50] [PMID: 22571616]
[28]
Jego G, Hazoumé A, Seigneuric R, Garrido C. Targeting heat shock proteins in cancer. Cancer Lett 2013; 332(2): 275-85.
[http://dx.doi.org/10.1016/j.canlet.2010.10.014] [PMID: 21078542]
[29]
Chatterjee S, Burns TF. Targeting heat shock proteins in cancer: a promising therapeutic approach. Int J Mol Sci 2017; 18(9)E1978
[http://dx.doi.org/10.3390/ijms18091978] [PMID: 28914774]
[30]
Jhaveri K, Taldone T, Modi S, Chiosis G. Advances in the clinical development of heat shock protein 90 (Hsp90) inhibitors in cancers. Biochim Biophys Acta 2012; 1823(3): 742-55.
[http://dx.doi.org/10.1016/j.bbamcr.2011.10.008] [PMID: 22062686]
[31]
Yuno A, Lee MJ, Lee S, et al. Clinical Evaluation and Biomarker Profiling of Hsp90 Inhibitors. Methods Mol Biol 2018; 1709: 423-41.
[http://dx.doi.org/10.1007/978-1-4939-7477-1_29] [PMID: 29177675]
[32]
Uehara Y. Natural product origins of Hsp90 inhibitors. Curr Cancer Drug Targets 2003; 3(5): 325-30.
[http://dx.doi.org/10.2174/1568009033481796] [PMID: 14529384]
[33]
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 USA 1994; 91(18): 8324-8.
[http://dx.doi.org/10.1073/pnas.91.18.8324] [PMID: 8078881]
[34]
Delmotte P, Delmotte-Plaque J. A new antifungal substance of fungal origin. Nature 1953; 171(4347): 344.
[http://dx.doi.org/10.1038/171344a0] [PMID: 13036885]
[35]
Schulte TW, Akinaga S, Soga S, et al. Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin. Cell Stress Chaperones 1998; 3(2): 100-8.
[http://dx.doi.org/10.1379/1466-1268(1998)003<0100:ARBTTN>2.3.CO;2] [PMID: 9672245]
[36]
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.
[http://dx.doi.org/10.1007/s002800050817] [PMID: 9744771]
[37]
Banerji U, O’Donnell A, Scurr M, et al. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygel- danamycin in patients with advanced malignancies. J Clin Oncol 2005; 23(18): 4152-61.
[http://dx.doi.org/10.1200/JCO.2005.00.612] [PMID: 15961763]
[38]
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 2010; 46(2): 340-7.
[http://dx.doi.org/10.1016/j.ejca.2009.10.026] [PMID: 19945858]
[39]
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 2010; 24(4): 699-705.
[http://dx.doi.org/10.1038/leu.2009.292] [PMID: 20111068]
[40]
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 USA 2006; 103(46): 17408-13.
[http://dx.doi.org/10.1073/pnas.0608372103] [PMID: 17090671]
[41]
Hanson BE, Vesole DH. Retaspimycin hydrochloride (IPI-504): a novel heat shock protein inhibitor as an anticancer agent. Expert Opin Investig Drugs 2009; 18(9): 1375-83.
[http://dx.doi.org/10.1517/13543780903158934] [PMID: 19642950]
[42]
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. Clin Cancer Res 2011; 17(17): 5604-14.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0562] [PMID: 21737509]
[43]
Cheung KM, Matthews TP, James K, et al. 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 2005; 15(14): 3338-43.
[http://dx.doi.org/10.1016/j.bmcl.2005.05.046] [PMID: 15955698]
[44]
Brough PA, Aherne W, Barril X, et al. 4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 2008; 51(2): 196-218.
[http://dx.doi.org/10.1021/jm701018h] [PMID: 18020435]
[45]
Eccles SA, Massey A, Raynaud FI, et al. NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 2008; 68(8): 2850-60.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-5256] [PMID: 18413753]
[46]
Woodhead AJ, Angove H, Carr MG, et al. 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 2010; 53(16): 5956-69.
[http://dx.doi.org/10.1021/jm100060b] [PMID: 20662534]
[47]
Nakashima T, Ishii T, Tagaya H, et al. New molecular and biological mechanism of antitumor activities of KW-2478, a novel nonansamycin heat shock protein 90 inhibitor, in multiple myeloma cells. Clin Cancer Res 2010; 16(10): 2792-802.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-3112] [PMID: 20406843]
[48]
Ying W, Du Z, Sun L, et al. Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy. Mol Cancer Ther 2012; 11(2): 475-84.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0755] [PMID: 22144665]
[49]
Taldone T, Chiosis G. Purine-scaffold Hsp90 inhibitors. Curr Top Med Chem 2009; 9(15): 1436-46.
[http://dx.doi.org/10.2174/156802609789895737] [PMID: 19860732]
[50]
Kasibhatla SR, Hong K, Biamonte MA, et al. Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity. J Med Chem 2007; 50(12): 2767-78.
[http://dx.doi.org/10.1021/jm050752+] [PMID: 17488003]
[51]
Hong D, Said R, Falchook G, et al. Phase I study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors. Clin Cancer Res 2013; 19(17): 4824-31.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0477] [PMID: 23873691]
[52]
Bao R, Lai CJ, Qu H, et al. CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy. Clin Cancer Res 2009; 15(12): 4046-57.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0152] [PMID: 19509149]
[53]
Caldas-Lopes E, Cerchietti L, Ahn JH, et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci USA 2009; 106(20): 8368-73.
[http://dx.doi.org/10.1073/pnas.0903392106] [PMID: 19416831]
[54]
Kim SH, Bajji A, Tangallapally R, et al. Discovery of (2S)-1-[4-(2-6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-ylethyl)piperidin-1-yl]-2-hydroxypropan-1-one (MPC-3100), a purine-based Hsp90 inhibitor. J Med Chem 2012; 55(17): 7480-501.
[http://dx.doi.org/10.1021/jm3004619] [PMID: 22913511]
[55]
Fadden P, Huang KH, Veal JM, et al. Application of chemoproteomics to drug discovery: identification of a clinical candidate targeting hsp90. Chem Biol 2010; 17(7): 686-94.
[http://dx.doi.org/10.1016/j.chembiol.2010.04.015] [PMID: 20659681]
[56]
Bussenius J, Blazey CM, Aay N, et al. Discovery of XL888: a novel tropane-derived small molecule inhibitor of HSP90. Bioorg Med Chem Lett 2012; 22(17): 5396-404.
[http://dx.doi.org/10.1016/j.bmcl.2012.07.052] [PMID: 22877636]
[57]
Ohkubo S, Kodama Y, Muraoka H, et al. TAS-116, a highly selective inhibitor of heat shock protein 90α and β, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models. Mol Cancer Ther 2015; 14(1): 14-22.
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0219] [PMID: 25416789]
[58]
McBride CM, Levine B, Xia Y, et al. Design, structure-activity relationship, and in vivo characterization of the development candidate NVP-HSP990. J Med Chem 2014; 57(21): 9124-9.
[http://dx.doi.org/10.1021/jm501107q] [PMID: 25368984]
[59]
Spreafico A, Delord JP, De Mattos-Arruda L, et al. A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies. Br J Cancer 2015; 112(4): 650-9.
[http://dx.doi.org/10.1038/bjc.2014.653] [PMID: 25625276]
[60]
Sun HP, Jia JM, Jiang F, et al. Identification and optimization of novel Hsp90 inhibitors with tetrahydropyrido[4,3-d]pyrimidines core through shape-based screening. Eur J Med Chem 2014; 79: 399-412.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.061] [PMID: 24763261]
[61]
Jiang F, Wang HJ, Jin YH, et al. Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90. J Med Chem 2016; 59(23): 10498-519.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00912] [PMID: 27933959]
[62]
Liang C, Hao H, Wu X, et al. Design and synthesis of N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-1,2,3,4-tetrahydroisoquinoline-3-carboxamides as novel Hsp90 inhibitors. Eur J Med Chem 2016; 121: 272-82.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.033] [PMID: 27266997]
[63]
Liang C, Wu X, Li Z, Zhu J, Lu C, Shen Y. Design, synthesis and pharmacological evaluation of N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-N-arylmethyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamides as potent Hsp90 inhibitors. Eur J Med Chem 2018; 143: 85-96.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.013] [PMID: 29172085]
[64]
Taldone T, Patel PD, Patel M, et al. Experimental and structural testing module to analyze paralogue-specificity and affinity in the Hsp90 inhibitors series. J Med Chem 2013; 56(17): 6803-18.
[http://dx.doi.org/10.1021/jm400619b] [PMID: 23965125]
[65]
Jeong JH, Oh YJ, Lho Y, et al. Targeting the entry region of Hsp90's ATP binding pocket with a novel 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl amide. Eur J Med Chem 2016; 124: 1069-80.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.038] [PMID: 27783977]
[66]
Jeong JH, Oh YJ, Kwon TK, Seo YH. Chalcone-templated Hsp90 inhibitors and their effects on gefitinib resistance in non-small cell lung cancer (NSCLC). Arch Pharm Res 2017; 40(1): 96-105.
[http://dx.doi.org/10.1007/s12272-016-0848-z] [PMID: 27770383]
[67]
Park SY, Oh YJ, Lho Y, et al. Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors. Eur J Med Chem 2018; 143: 390-401.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.054] [PMID: 29202402]
[68]
Huang R, Ayine-Tora DM, Muhammad Rosdi MN, Li Y, Reynisson J, Leung IKH. Virtual screening and biophysical studies lead to HSP90 inhibitors. Bioorg Med Chem Lett 2017; 27(2): 277-81.
[http://dx.doi.org/10.1016/j.bmcl.2016.11.059] [PMID: 27913182]
[69]
Geng K, Liu H, Song Z, et al. Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs. Eur J Med Chem 2018; 152: 76-86.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.019] [PMID: 29698859]
[70]
Sharma GG, Mota I, Mologni L, Patrucco E, Gambacorti-Passerini C, Chiarle R. Tumor Resistance against ALK Targeted Therapy-Where It Comes From and Where It Goes. Cancers (Basel) 2018; 10(3): 62.
[http://dx.doi.org/10.3390/cancers10030062] [PMID: 29495603]
[71]
Lee JH, Shin SC, Seo SH, et al. Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors. Bioorg Med Chem Lett 2017; 27(2): 237-41.
[http://dx.doi.org/10.1016/j.bmcl.2016.11.062] [PMID: 27914802]
[72]
Uno T, Kawai Y, Yamashita S, et al. Discovery of 3-Ethyl-4-(3-isopropyl-4-(4-(1-methyl-1 H-pyrazol-4-yl)-1 H-imidazol-1-yl)-1 H-pyrazolo[3,4- b]pyridin-1-yl)benzamide (TAS-116) as a Potent, Selective, and Orally Available HSP90 Inhibitor. J Med Chem 2019; 62(2): 531-51.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01085] [PMID: 30525599]
[73]
Kurokawa Y, Doi T, Sawaki A, et al. Phase II study of TAS-116, an oral inhibitor of heat shock protein 90 (HSP90), in metastatic or unresectable gastrointestinal stromal tumor refractory to imatinib, sunitinib and regorafenib. Ann Oncol 2017; 28: 522-3.
[http://dx.doi.org/10.1093/annonc/mdx387.006]
[74]
Bai S-Y, Dai X, Zhao B-X, Miao J-Y. Discovery of a novel fluorescent HSP90 inhibitor and its anti-lung cancer effect. RSC Advances 2014; 4(38): 19887-90.
[http://dx.doi.org/10.1039/C4RA01800A]
[75]
Wei Q, Ning JY, Dai X, et al. Discovery of novel HSP90 inhibitors that induced apoptosis and impaired autophagic flux in A549 lung cancer cells. Eur J Med Chem 2018; 145: 551-8.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.024] [PMID: 29339250]
[76]
Virelli M, Moroni E, Colombo G, et al. Expedient access to 2-benzazepines by palladium-catalyzed c-h activation: identification of a unique hsp90 inhibitor scaffold. Chemistry 2018; 24(62): 16516-20.
[http://dx.doi.org/10.1002/chem.201804244] [PMID: 30136746]
[77]
Koca İ, Özgür A, Er M, Gümüş M, Açikalin Coşkun K, Tutar Y. Design and synthesis of pyrimidinyl acyl thioureas as novel Hsp90 inhibitors in invasive ductal breast cancer and its bone metastasis. Eur J Med Chem 2016; 122: 280-90.
[http://dx.doi.org/10.1016/j.ejmech.2016.06.032] [PMID: 27376491]
[78]
Liu Y, Liu X, Li L, et al. Identification and Structure-Activity Studies of 1,3-Dibenzyl-2-aryl imidazolidines as Novel Hsp90 Inhibitors. Molecules 2019; 24(11): 2105.
[http://dx.doi.org/10.3390/molecules24112105] [PMID: 31163701]
[79]
Garnier C, Lafitte D, Tsvetkov PO, et al. Binding of ATP to heat shock protein 90: evidence for an ATP-binding site in the C-terminal domain. J Biol Chem 2002; 277(14): 12208-14.
[http://dx.doi.org/10.1074/jbc.M111874200] [PMID: 11805114]
[80]
Bagatell R, Paine-Murrieta GD, Taylor CW, et al. Induction of a heat shock factor 1-dependent stress response alters the cytotoxic activity of hsp90-binding agents. Clin Cancer Res 2000; 6(8): 3312-8.
[PMID: 10955818]
[81]
Piper PW, Millson SH. Mechanisms of resistance to hsp90 inhibitor drugs: a complex mosaic emerges. Pharmaceuticals (Basel) 2011; 4(11): 1400-22.
[http://dx.doi.org/10.3390/ph4111400] [PMID: 27721330]
[82]
Wang Y, Koay YC, McAlpine SR. How Selective are Hsp90 Inhibitors for Cancer Cells over Normal Cells? ChemMedChem 2017; 12(5): 353-7.
[http://dx.doi.org/10.1002/cmdc.201600595] [PMID: 28139075]
[83]
Donnelly A, Blagg BS. Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr Med Chem 2008; 15(26): 2702-17.
[http://dx.doi.org/10.2174/092986708786242895] [PMID: 18991631]
[84]
Marcu MG, Schulte TW, Neckers L. Novobiocin and related coumarins and depletion of heat shock protein 90-dependent signaling proteins. J Natl Cancer Inst 2000; 92(3): 242-8.
[http://dx.doi.org/10.1093/jnci/92.3.242] [PMID: 10655441]
[85]
Shelton SN, Shawgo ME, Matthews SB, et al. KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kDa heat shock protein, exerts potent antiproliferative effects in human leukemic cells. Mol Pharmacol 2009; 76(6): 1314-22.
[http://dx.doi.org/10.1124/mol.109.058545] [PMID: 19741006]
[86]
Zhao H, Donnelly AC, Kusuma BR, et al. Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti-proliferative agents. J Med Chem 2011; 54(11): 3839-53.
[http://dx.doi.org/10.1021/jm200148p] [PMID: 21553822]
[87]
Zhao H, Moroni E, Colombo G, Blagg BS. Identification of a new scaffold for hsp90 C-terminal inhibition. ACS Med Chem Lett 2013; 5(1): 84-8.
[http://dx.doi.org/10.1021/ml400404s] [PMID: 24900777]
[88]
Kusuma BR, Khandelwal A, Gu W, et al. Synthesis and biological evaluation of coumarin replacements of novobiocin as Hsp90 inhibitors. Bioorg Med Chem 2014; 22(4): 1441-9.
[http://dx.doi.org/10.1016/j.bmc.2013.12.056] [PMID: 24461493]
[89]
Garg G, Zhao H, Blagg BS. Design, synthesis and biological evaluation of alkylamino biphenylamides as Hsp90 C-terminal inhibitors. Bioorg Med Chem 2017; 25(2): 451-7.
[http://dx.doi.org/10.1016/j.bmc.2016.11.030] [PMID: 27914946]
[90]
Garg G, Forsberg LK, Zhao H, Blagg BSJ. Development of Phenyl Cyclohexylcarboxamides as a Novel Class of Hsp90 C-terminal Inhibitors. Chemistry 2017; 23(65): 16574-85.
[http://dx.doi.org/10.1002/chem.201703206] [PMID: 28940589]
[91]
Forsberg LK, Liu W, Holzbeierlein J, Blagg BSJ. Modified biphenyl Hsp90 C-terminal inhibitors for the treatment of cancer. Bioorg Med Chem Lett 2017; 27(18): 4514-9.
[http://dx.doi.org/10.1016/j.bmcl.2017.07.030] [PMID: 28844386]
[92]
Jiang F, Guo AP, Xu JC, et al. Identification and optimization of novel 6-acylamino-2-aminoquinolines as potent Hsp90 C-terminal inhibitors. Eur J Med Chem 2017; 141: 1-14.
[http://dx.doi.org/10.1016/j.ejmech.2017.07.080] [PMID: 29028527]
[93]
Chang DJ, An H, Kim KS, et al. Design, synthesis, and biological evaluation of novel deguelin-based heat shock protein 90 (HSP90) inhibitors targeting proliferation and angiogenesis. J Med Chem 2012; 55(24): 10863-84.
[http://dx.doi.org/10.1021/jm301488q] [PMID: 23186287]
[94]
Lee SC, Min HY, Choi H, et al. Deguelin analogue sh-1242 inhibits hsp90 activity and exerts potent anticancer efficacy with limited neurotoxicity. Cancer Res 2016; 76(3): 686-99.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-1492] [PMID: 26645561]
[95]
Kim HS, Hong M, Lee SC, et al. Ring-truncated deguelin derivatives as potent Hypoxia Inducible Factor-1α (HIF-1α) inhibitors. Eur J Med Chem 2015; 104: 157-64.
[http://dx.doi.org/10.1016/j.ejmech.2015.09.033] [PMID: 26457742]
[96]
Kim HS, Hong M, Ann J, et al. Synthesis and biological evaluation of C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors. Bioorg Med Chem 2016; 24(22): 6082-93.
[http://dx.doi.org/10.1016/j.bmc.2016.09.067] [PMID: 27745993]
[97]
Hyun SY, Le HT, Nguyen CT, et al. Development of a novel Hsp90 inhibitor NCT-50 as a potential anticancer agent for the treatment of non-small cell lung cancer. Sci Rep 2018; 8(1): 13924.
[http://dx.doi.org/10.1038/s41598-018-32196-6] [PMID: 30224681]
[98]
Chini MG, Malafronte N, Vaccaro MC, et al. identification of limonol derivatives as heat shock protein 90 (hsp90) inhibitors through a multidisciplinary approach. Chemistry 2016; 22(37): 13236-50.
[http://dx.doi.org/10.1002/chem.201602242] [PMID: 27492719]
[99]
Le HT, Nguyen HT, Min HY, et al. Panaxynol, a natural Hsp90 inhibitor, effectively targets both lung cancer stem and non-stem cells. Cancer Lett 2018; 412: 297-307.
[http://dx.doi.org/10.1016/j.canlet.2017.10.013] [PMID: 29061506]
[100]
Gewirth DT. Paralog specific hsp90 inhibitors - a brief history and a bright future. Curr Top Med Chem 2016; 16(25): 2779-91.
[http://dx.doi.org/10.2174/1568026616666160413141154] [PMID: 27072700]
[101]
Duerfeldt AS, Peterson LB, Maynard JC, et al. Development of a Grp94 inhibitor. J Am Chem Soc 2012; 134(23): 9796-804.
[http://dx.doi.org/10.1021/ja303477g] [PMID: 22642269]
[102]
Muth A, Crowley V, Khandelwal A, et al. Development of radamide analogs as Grp94 inhibitors. Bioorg Med Chem 2014; 22(15): 4083-98.
[http://dx.doi.org/10.1016/j.bmc.2014.05.075] [PMID: 25027801]
[103]
Crowley VM, Khandelwal A, Mishra S, et al. Development of glucose regulated protein 94-selective inhibitors based on the bnim and radamide scaffold. J Med Chem 2016; 59(7): 3471-88.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00085] [PMID: 27003516]
[104]
Crowley VM, Huard DJE, Lieberman RL, Blagg BSJ. Second generation grp94-selective inhibitors provide opportunities for the inhibition of metastatic cancer. Chemistry 2017; 23(62): 15775-82.
[http://dx.doi.org/10.1002/chem.201703398] [PMID: 28857290]
[105]
Patel PD, Yan P, Seidler PM, et al. Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol 2013; 9(11): 677-84.
[http://dx.doi.org/10.1038/nchembio.1335] [PMID: 23995768]
[106]
Patel HJ, Patel PD, Ochiana SO, et al. Structure-activity relationship in a purine-scaffold compound series with selectivity for the endoplasmic reticulum Hsp90 paralog Grp94. J Med Chem 2015; 58(9): 3922-43.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00197] [PMID: 25901531]
[107]
Mishra SJ, Ghosh S, Stothert AR, Dickey CA, Blagg BS. Transformation of the non-selective aminocyclohexanol-based hsp90 inhibitor into a grp94-seletive scaffold. ACS Chem Biol 2017; 12(1): 244-53.
[http://dx.doi.org/10.1021/acschembio.6b00747] [PMID: 27959508]
[108]
Jiang F, Guo AP, Xu JC, You QD, Xu XL. Discovery of a potent grp94 selective inhibitor with anti-inflammatory efficacy in a mouse model of ulcerative colitis. J Med Chem 2018; 61(21): 9513-33.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00800] [PMID: 30351001]
[109]
Roger J, Hausmann M, Rogler G. The role of the chaperone grp94/gp96 in the intestinal barrier and innate immune functions. Curr Immunol Rev 2017; 13(1): 64-70.
[110]
Khandelwal A, Kent CN, Balch M, et al. Structure-guided design of an Hsp90β N-terminal isoform-selective inhibitor. Nat Commun 2018; 9(1): 425.
[http://dx.doi.org/10.1038/s41467-017-02013-1] [PMID: 29382832]
[111]
Verba KA, Wang RY, Arakawa A, et al. Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase. Science 2016; 352(6293): 1542-7.
[http://dx.doi.org/10.1126/science.aaf5023] [PMID: 27339980]
[112]
Lu X, Xiao L, Wang L, Ruden DM. Hsp90 inhibitors and drug resistance in cancer: the potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs. Biochem Pharmacol 2012; 83(8): 995-1004.
[http://dx.doi.org/10.1016/j.bcp.2011.11.011] [PMID: 22120678]
[113]
Heske CM, Mendoza A, Edessa LD, et al. STA-8666, a novel HSP90 inhibitor/SN-38 drug conjugate, causes complete tumor regression in preclinical mouse models of pediatric sarcoma. Oncotarget 2016; 7(40): 65540-52.
[http://dx.doi.org/10.18632/oncotarget.11869] [PMID: 27608846]
[114]
Proia DA, Kaufmann GF. Targeting heat-shock protein 90 (hsp90) as a complementary strategy to immune checkpoint blockade for cancer therapy. Cancer Immunol Res 2015; 3(6): 583-9.
[http://dx.doi.org/10.1158/2326-6066.CIR-15-0057] [PMID: 25948551]
[115]
Mbofung RM, McKenzie JA, Malu S, et al. HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. Nat Commun 2017; 8(1): 451.
[http://dx.doi.org/10.1038/s41467-017-00449-z] [PMID: 28878208]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 21
ISSUE: 3
Year: 2020
Page: [302 - 317]
Pages: 16
DOI: 10.2174/1389450120666190829162544
Price: $65

Article Metrics

PDF: 34
HTML: 1