Abstract
The role of the Hsp70 molecular chaperone in effecting proper cellular protein folding, transport, and degradation processes, stabilizing protein complexes, and maintaining membrane integrity has long been recognized. More recently, Hsp70 has been linked to severe neurological diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease, as well as to cystic fibrosis and cancer. As a result, there is a growing interest in the development of small-molecule modulators of Hsp70 function. While several distinct classes of Hsp70 agonists and antagonists have been identified to date, clinical studies with Hsp70-targeted drugs have yet to be initiated, and proof of principle for therapeutic benefits remains to be established. However, a large body of preclinical biological evidence suggests that this chaperone plays a key role in many human diseases associated with protein (un)folding and trafficking and that the continued development of Hsp70 modulators will yield novel therapeutic strategies.
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References
Ensembl (2013) Human assembly and gene annotation. http://Jan2013.archive.ensembl.org/Homo_sapiens/Info/Annotation/. Accessed 20 Feb 2013
Flicek P, Amode MR, Barrell D et al (2012) Ensembl 2012. Nucleic Acids Res 40:D84–D90
Walsh CT, Garneau-Tsodikova S, Gatto GJ (2005) Protein posttranslational modifications: the chemistry of proteome diversifications. Angew Chem Int Ed 44:7342–7372
Marko-Varga G, Omenn GS, Paik Y-K et al (2013) A first step toward completion of a genome-wide characterization of the human proteome. J Proteome Res 12:1–5
Fulda S, Gorman AM, Hori O et al (2010) Cellular stress responses: cell survival and cell death. Int J Cell Biol 2010:214074. doi:10.1155/2010/214074
Chaudhuri TK, Paul S (2006) Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J 273:1331–1349
Rutkowski DT, Hegde RS (2010) Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol 189:783–794
Ellis J (1987) Proteins as molecular chaperones. Nature 328:378–379
Lee AS (1987) Coordinated regulation of a set of genes by glucose and calcium ionophores in mammalian cells. Trends Biochem Sci 12:20–23
Frydman J (2001) Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem 70:603
Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858
McClellan AJ, Frydman J (2001) Molecular chaperones and the art of recognizing a lost cause. Nat Cell Biol 3:E51
Jolly C, Morimoto RI (2000) Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst 92:1564–1572
Pelham HRB (1986) Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell 46:959–961
Yao T-P (2010) The role of ubiquitin in autophagy-dependent protein aggregate processing. Genes Cancer 1:779–786
Gamerdinger M, Carra S, Behl C (2011) Emerging roles of molecular chaperones and co-chaperones in selective autophagy: focus on BAG proteins. J Mol Med 89:1175–1182
Kaushik S, Bandyopadhyay U, Sridhar S et al (2011) Chaperone-mediated autophagy at a glance. J Cell Sci 124:495–499
Powers MV, Workman P (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581:3758–3769
Calderwood SK, Stevenson MA, Murshid A (2012) Heat shock proteins, autoimmunity, and cancer treatment. Autoimmune Dis 2012:10
Murphy ME (2013) The HSP70 family and cancer. Carcinogenesis 34:1181–1188
Sherman MY, Gabai VL (2014) Hsp70 in cancer: back to the future. Oncogene. doi:10.1038/onc.2014.349
Massey AJ (2010) ATPases as drug targets: insights from heat shock proteins 70 and 90. J Med Chem 53:7280–7286
Yamaki H, Nakajima M, Shimotohno KW et al (2011) Molecular basis for the actions of Hsp90 inhibitors and cancer therapy. J Antibiot (Tokyo) 64:635–644
Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772
Neckers L (2007) Heat shock protein 90: the cancer chaperone. J Biosci 32:517–530
Patel HJ, Modi S, Chiosis G et al (2011) Advances in the discovery and development of heat-shock protein 90 inhibitors for cancer treatment. Expert Opin Drug Discov 6:559–587
Zhang H, Burrows F (2004) Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med 82:488–499
Wayne N, Mishra P, Bolon DN (2011) Hsp90 and client protein maturation. In: Calderwood SK, Prince TL (eds) Molecular chaperones: methods and protocols, vol 787, Methods in molecular biology. Springer, New York, pp 33–44
Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–294
DeBoer C, Meulman PA, Wnuk RJ et al (1970) Geldanamycin, a new antibiotic. J Antibiot (Tokyo) 23:442–447
Stebbins CE, Russo AA, Schneider C et al (1997) Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 89:239–250
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
Den RB, Lu B (2012) Heat shock protein 90 inhibition: rationale and clinical potential. Ther Adv Med Oncol 4:211–218
Whitesell L, Lin NU (2012) HSP90 as a platform for the assembly of more effective cancer chemotherapy. BBA Mol Cell Res 1823:756–766
Solit DB, Basso AD, Olshen AB et al (2003) Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to taxol. Cancer Res 63:2139–2144
Kamal A, Thao L, Sensintaffar J et al (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410
García-Morales P, Carrasco-García E, Ruiz-Rico P et al (2007) Inhibition of Hsp90 function by ansamycins causes downregulation of cdc2 and cdc25c and G2/M arrest in glioblastoma cell lines. Oncogene 26:7185–7193
Wang Y, Trepel JB, Neckers LM et al (2010) STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs 11:1466–1476
Brough PA, Aherne W, Barril X et al (2007) 4,5-Diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem 51:196–218
Eccles SA, Massey A, Raynaud FI et al (2008) NVP-AUY922: a novel heat shock protein 90 inhibitor active against xenograft tumor growth, angiogenesis, and metastasis. Cancer Res 68:2850–2860
Garon EB, Finn RS, Hamidi H et al (2013) The HSP90 inhibitor NVP-AUY922 potently inhibits non–small cell lung cancer growth. Mol Cancer Ther 12:890–900
Gallegos Ruiz MI, Floor K, Roepman P et al (2008) Integration of gene dosage and gene expression in non-small cell lung cancer, identification of HSP90 as potential target. PLoS One 3:e0001722
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
Guo F, Rocha K, Bali P et al (2005) Abrogation of heat shock protein 70 induction as a strategy to increase antileukemia activity of heat shock protein 90 inhibitor 17-allylamino-demethoxy geldanamycin. Cancer Res 65:10536–10544
Cui XB, Yu ZY, Wang W et al (2012) Co-inhibition of HSP70/HSP90 synergistically sensitizes nasopharyngeal carcinoma cells to thermotherapy. Integr Cancer Ther 11:61–67
Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124
Brodsky JL, Chiosis G (2006) Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulators. Curr Top Med Chem 6:1215–1225
Buck TM, Wright CM, Brodsky JL (2007) The activities and function of molecular chaperones in the endoplasmic reticulum. Semin Cell Dev Biol 18:751–761
Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125:443–451
Fewell SW, Travers KJ, Weissman JS et al (2001) The action of molecular chaperones in the early secretory pathway. Annu Rev Genet 35:149–191
Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670–684
Massey AC, Zhang C, Cuervo AM (2006) Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 73:205–235
Evans CG, Wisen S, Gestwicki JE (2006) Heat shock proteins 70 and 90 inhibit early stages of amyloid beta-(1-42) aggregation in vitro. J Biol Chem 281:33182–33191
Kirkegaard T, Roth AG, Petersen NH et al (2010) Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature 463:549–553
Brodsky JL (2001) Chaperoning the maturation of the cystic fibrosis transmembrane conductance regulator. Am J Physiol Lung Cell Mol Physiol 281:L39–L42
Turturici G, Sconzo G, Geraci F (2011) Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. doi:10.1155/2011/618127
Abisambra J, Jinwal UK, Miyata Y et al (2013) Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau. Biol Psychiatry. doi:10.1016/j.biopsych.2013.02.027
Carmichael J, Chatellier J, Woolfson A et al (2000) Bacterial and yeast chaperones reduce both aggregate formation and cell death in mammalian cell models of Huntington’s disease. Proc Natl Acad Sci U S A 97:9701–9705
Jana NR, Tanaka M, Wang G-h et al (2000) Polyglutamine length-dependent interaction of Hsp40 and Hsp70 family chaperones with truncated N-terminal huntingtin: their role in suppression of aggregation and cellular toxicity. Hum Mol Genet 9:2009–2018
Witt SN (2010) Hsp70 molecular chaperones and Parkinson’s disease. Biopolymers 93:218–228
Cho HJ, Gee HY, Baek K-H et al (2011) A small molecule that binds to an ATPase domain of Hsc70 promotes membrane trafficking of mutant cystic fibrosis transmembrane conductance regulator. J Am Chem Soc 133:20267–20276
Boorstein WR, Ziegelhoffer T, Craig EA (1994) Molecular evolution of the HSP70 multigene family. J Mol Evol 38:1–17
Rensing SA, Maier UG (1994) Phylogenetic analysis of the stress-70 protein family. J Mol Evol 39:80–86
Daugaard M, Rohde M, Jäättelä M (2007) The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett 581:3702–3710
Hunt C, Morimoto RI (1985) Conserved features of eukaryotic hsp70 genes revealed by comparison with the nucleotide sequence of human hsp70. Proc Natl Acad Sci U S A 82:6455–6459
Bardwell JC, Craig EA (1984) Major heat shock gene of Drosophila and the Escherichia coli heat-inducible dnaK gene are homologous. Proc Natl Acad Sci U S A 81:848–852
Flaherty KM, DeLuca-Flaherty C, McKay DB (1990) Three-dimensional structure of the ATPase fragment of a 70k heat-shock cognate protein. Nature 346:623–628
Normington K, Kohno K, Kozutsumi Y et al (1989) S. cerevisiae encodes an essential protein homologous in sequence and function to mammalian BiP. Cell 57:1223–1236
Zhu X, Zhao X, Furkholder WF et al (1996) Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272:1606–1614
Freeman BC, Myers MP, Schumacher R et al (1995) Identification of a regulatory motif in Hsp70 that affects ATPase activity, substrate binding and interaction with HDJ-1. EMBO J 14:2281–2292
Allan RK, Ratajczak T (2011) Versatile TPR domains accommodate different modes of target protein recognition and function. Cell Stress Chaperones 16:353–367
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
Zhuravleva A, Clerico EM, Gierasch LM (2012) An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell 151:1296–1307
Cyr DM (2008) Swapping nucleotides, tuning Hsp70. Cell 133:945–947
Kityk R, Kopp J, Sinning I et al (2012) Structure and dynamics of the ATP-bound open conformation of Hsp70 chaperones. Mol Cell 48:863–874
Swain JF, Dinler G, Sivendran R et al (2007) Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker. Mol Cell 26:27–39
Zhang Y, Zuiderweg ERP (2004) The 70-kDa heat shock protein chaperone nucleotide-binding domain in solution unveiled as a molecular machine that can reorient its functional subdomains. Proc Natl Acad Sci U S A 101:10272–10277
Pellecchia M, Montgomery DL, Stevens SY et al (2000) Structural insights into substrate binding by the molecular chaperone DnaK. Nat Struct Biol 7:298–303
Slepenkov SV, Witt SN (2002) Kinetic analysis of interdomain coupling in a lidless variant of the molecular chaperone DnaK: DnaK’s lid inhibits transition to the low affinity state. Biochemistry 41:12224–12235
Qi R, Sarbeng EB, Liu Q et al (2013) Allosteric opening of the polypeptide-binding site when an Hsp70 binds ATP. Nat Struct Mol Biol 20:900–907
Bertelsen EB, Chang L, Gestwicki JE et al (2009) Solution conformation of wild-type E. coli Hsp70 (DnaK) chaperone complexed with ADP and substrate. Proc Natl Acad Sci U S A 106:8471–8476
Kelley WL (1998) The J-domain family and the recruitment of chaperone power. Trends Biochem Sci 23:222–227
Laufen T, Mayer MP, Beisel C et al (1999) Mechanism of regulation of hsp70 chaperones by DnaJ cochaperones. Proc Natl Acad Sci U S A 96:5452–5457
Jiang J, Maes EG, Taylor AB et al (2007) Structural basis of J cochaperone binding and regulation of Hsp70. Mol Cell 28:422–433
Suh W-C, Burkholder WF, Lu CZ et al (1998) Interaction of the Hsp70 molecular chaperone, DnaK, with its cochaperone DnaJ. Proc Natl Acad Sci U S A 95:15223–15228
Gässler CS, Buchberger A, Laufen T et al (1998) Mutations in the DnaK chaperone affecting interaction with the DnaJ cochaperone. Proc Natl Acad Sci U S A 95:15229–15234
Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11:579–592
Kota P, Summers DW, Ren HY et al (2009) Identification of a consensus motif in substrates bound by a Type I Hsp40. Proc Natl Acad Sci U S A 106:11073–11078
Craig EA, Huang P, Aron R et al (2006) The diverse roles of J-proteins, the obligate Hsp70 co-chaperone. In: Amara SG, Bamberg E, Grinstein S et al (eds) Reviews of physiology, biochemistry and pharmacology, vol 156. Springer, Berlin, pp 1–21. doi:10.1007/s10254-005-0001-0
Schroder H, Langer T, Hartl FU et al (1993) DnaK, DnaJ and GrpE form a cellular chaperone machinery capable of repairing heat-induced protein damage. EMBO J 12:4137–4144
Polier S, Dragovic Z, Hartl FU et al (2008) Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein folding. Cell 133:1068–1079
Tzankov S, Wong MJH, Shi K et al (2008) Functional divergence between co-chaperones of Hsc70. J Biol Chem 283:27100–27109
Shaner L, Morano KA (2007) All in the family: atypical Hsp70 chaperones are conserved modulators of Hsp70 activity. Cell Stress Chaperones 12:1–8
Schuermann JP, Jiang J, Cuellar J et al (2008) Structure of the Hsp110:Hsc70 nucleotide exchange machine. Mol Cell 31:232–243
Brocchieri L, Conway dME, Macario AJL (2008) Hsp70 genes in the human genome: conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol 8:19
Wu B, Hunt C, Morimoto R (1985) Structure and expression of the human gene encoding major heat shock protein HSP70. Mol Cell Biol 5:330–341
Tavaria M, Gabriele T, Kola I et al (1996) A hitchhiker’s guide to the human Hsp70 family. Cell Stress Chaperones 1:23–28
Hageman J, Kampinga HH (2009) Computational analysis of the human HSPH/HSPA/DNAJ family and cloning of a human HSPH/HSPA/DNAJ expression library. Cell Stress Chaperones 14:1–21
Wu C (1995) Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol 11:441–469
Calderwood SK, Xie Y, Wang X et al (2010) Signal transduction pathways leading to heat shock transcription. Sign Transduct Insights 2:13–24
Hunt CR, Dix DJ, Sharma GG et al (2004) Genomic instability and enhanced radiosensitivity in Hsp70.1- and Hsp70.3-deficient mice. Mol Cell Biol 24:899–911
Werner-Washburne M, Becker J, Kosic-Smithers J et al (1989) Yeast Hsp70 RNA levels vary in response to the physiological status of the cell. J Bacteriol 171:2680–2688
Werner-Washburne M, Stone DE, Craig EA (1987) Complex interactions among members of an essential subfamily of hsp70 genes in Saccharomyces cerevisiae. Mol Cell Biol 7:2568–2577
Calloni G, Chen T, Schermann Sonya M et al (2012) DnaK functions as a central hub in the E. coli chaperone network. Cell Rep 1:251–264
Leung TK, Rajendran MY, Monfries C et al (1990) The human heat-shock protein family. Expression of a novel heat-inducible HSP70 (HSP70B’) and isolation of its cDNA and genomic DNA. Biochem J 267:125–132
Parsian AJ, Sheren JE, Tao TY et al (2000) The human Hsp70B gene at the HSPA7 locus of chromosome 1 is transcribed but non-functional. BBA Gene Struct Exp 1494:201–205
Su AI, Wiltshire T, Batalov S et al (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 101:6062–6067
Liu T, Daniels CK, Cao S (2012) Comprehensive review on the HSC70 functions, interactions with related molecules and involvement in clinical diseases and therapeutic potential. Pharmacol Ther 136:354–374
Dworniczak B, Mirault ME (1987) Structure and expression of a human gene coding for a 71 kd heat shock ‘cognate’ protein. Nucleic Acids Res 15:5181–5197
Huang L, Mivechi NF, Moskophidis D (2001) Insights into regulation and function of the major stress-induced hsp70 molecular chaperone in vivo: analysis of mice with targeted gene disruption of the hsp70.1 or hsp70.3 gene. Mol Cell Biol 21:8575–8591
Florin L, Becker KA, Sapp C et al (2004) Nuclear translocation of papillomavirus minor capsid protein L2 requires Hsc70. J Virol 78:5546–5553
Bonnycastle LLC, Yu C-E, Hunt CR et al (1994) Cloning, sequencing, and mapping of the human chromosome 14 heat shock protein gene (HSPA2). Genomics 23:85–93
Dix DJ, Allen JW, Collins BW et al (1996) Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility. Proc Natl Acad Sci U S A 93:3264–3268
Munro S, Pelham HRB (1986) An hsp70-like protein in the ER: identity with the 78 kd glucose-regulated protein and immunoglobulin heavy chain binding protein. Cell 46:291–300
Munro S, Pelham HRB (1987) A C-terminal signal prevents secretion of luminal ER proteins. Cell 48:899–907
Haas IG (1994) BiP (GRP78), an essential hsp70 resident protein in the endoplasmic reticulum. Experientia 50:1012–1020
Consortium TU (2012) Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res 40:D71–D75
Bhattacharyya T, Karnezis AN, Murphy SP et al (1995) Cloning and subcellular localization of human mitochondrial hsp70. J Biol Chem 270:1705–1710
Mizzen LA, Chang C, Garrels JI et al (1989) Identification, characterization, and purification of two mammalian stress proteins present in mitochondria, grp 75, a member of the hsp 70 family and hsp 58, a homolog of the bacterial groEL protein. J Biol Chem 264:20664–20675
Deocaris CC, Kaul SC, Wadhwa R (2006) On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60. Cell Stress Chaperones 11:116–128
Omura T (1998) Mitochondria-targeting sequence, a multi-role sorting sequence recognized at all steps of protein import into mitochondria. J Biochem 123:1010–1016
Craig EA, Kramer J, Shilling J et al (1989) SSC1, an essential member of the yeast HSP70 multigene family, encodes a mitochondrial protein. Mol Cell Biol 9:3000–3008
Bukau B, Deuerling E, Pfund C et al (2000) Getting newly synthesized proteins into shape. Cell 101:119–122
Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332
Eichmann C, Preissler S, Riek R et al (2010) Cotranslational structure acquisition of nascent polypeptides monitored by NMR spectroscopy. Proc Natl Acad Sci U S A 107:9111–9116
Elcock AH (2006) Molecular simulations of cotranslational protein folding: fragment stabilities, folding cooperativity, and trapping in the ribosome. PLoS Comput Biol 2:e98
Slepenkov SV, Witt SN (2002) The unfolding story of the Escherichia coli Hsp70 DnaK: is DnaK a holdase or an unfoldase? Mol Microbiol 45:1197–1206
Lu Z, Cyr DM (1998) The conserved carboxyl terminus and zinc finger-like domain of the co-chaperone Ydj1 assist Hsp70 in protein folding. J Biol Chem 273:5970–5978
Yan W, Schilke B, Pfund C et al (1998) Zuotin, a ribosome-associated DnaJ molecular chaperone. EMBO J 17:4809–4817
Höhfeld J, Minami Y, Hartl F-U (1995) Hip, a novel cochaperone involved in the eukaryotic hsc70/hsp40 reaction cycle. Cell 83:589–598
Hohfeld J, Jentsch S (1997) GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J 16:6209–6216
Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92:351–366
Sigler PB, Xu Z, Rye HS et al (1998) Structure and function in GroEL-mediated protein-folding. Annu Rev Biochem 67:581
Cuellar J, Martin-Benito J, Scheres SH et al (2008) The structure of CCT-Hsc70 NBD suggests a mechanism for Hsp70 delivery of substrates to the chaperonin. Nat Struct Mol Biol 15:858–864
Rosenzweig R, Moradi S, Zarrine-Afsar A et al (2013) Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction. Science 339:1080–1083
Glover JR, Lindquist S (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94:73–82
Seyffer F, Kummer E, Oguchi Y et al (2012) Hsp70 proteins bind Hsp100 regulatory M domains to activate AAA+ disaggregase at aggregate surfaces. Nat Struct Mol Biol 19:1347–1355
Goloubinoff P, Mogk A, Zvi APB et al (1999) Sequential mechanism of solubilization and refolding of stable protein aggregates by a bichaperone network. Proc Natl Acad Sci U S A 96:13732–13737
Ben-Zvi A, De Los Rios P, Dietler G et al (2004) Active solubilization and refolding of stable protein aggregates by cooperative unfolding action of individual Hsp70 chaperones. J Biol Chem 279:37298–37303
Diamant S, Ben-Zvi AP, Bukau B et al (2000) Size-dependent disaggregation of stable protein aggregates by the DnaK chaperone machinery. J Biol Chem 275:21107–21113
Rampelt H, Kirstein-Miles J, Nillegoda NB et al (2012) Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. EMBO J 31:4221
Shi Y, Thomas JO (1992) The transport of proteins into the nucleus requires the 70-kilodalton heat shock protein or its cytosolic cognate. Mol Cell Biol 12:2186–2192
Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev 18:306–360
Patterson C, Höhfeld J (2008) Molecular chaperones and the ubiquitin–proteasome system. Protein science encyclopedia. Wiley-VCH, Weinheim, pp 1–30. doi:10.1002/9783527610754.dd03
Hernández MP, Sullivan WP, Toft DO (2002) The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone complex. J Biol Chem 277:38294–38304
Pratt WB, Toft DO (2003) Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med 228:111–133
Terlecky SR, Chiang HL, Olson TS et al (1992) Protein and peptide binding and stimulation of in vitro lysosomal proteolysis by the 73-kDa heat shock cognate protein. J Biol Chem 267:9202–9209
McDonough H, Patterson C (2003) CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 8:303–308
Ballinger CA, Connell P, Wu Y et al (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19:4535–4545
Jiang J, Ballinger CA, Wu Y et al (2001) CHIP Is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J Biol Chem 276:42938–42944
Demand J, Alberti S, Patterson C et al (2001) Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol 11:1569–1577
Lüders J, Demand J, Höhfeld J (2000) The ubiquitin-related BAG-1 provides a link between the molecular chaperones Hsc70/Hsp70 and the proteasome. J Biol Chem 275:4613–4617
Mosser DD, Caron AW, Bourget L et al (2000) The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol 20:7146–7159
Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (Hsp70) as an emerging drug target. J Med Chem 53:4585–4602
Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516
Salomoni P, Khelifi AF (2006) Daxx: death or survival protein? Trends Cell Biol 16:97–104
Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27:6245–6251
Korsmeyer SJ, Wei MC, Saito M et al (2000) Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c. Cell Death Differ 7:1166–1173
Schmitt E, Gehrmann M, Brunet M et al (2007) Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol 81:15–27
Zorzi E, Bonvini P (2011) Inducible Hsp70 in the regulation of cancer cell survival: analysis of chaperone induction, expression and activity. Cancer 3:3921–3956
Stankiewicz AR, Lachapelle G, Foo CPZ et al (2005) Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 280:38729–38739
Ruchalski K, Mao H, Li Z et al (2006) Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation. J Biol Chem 281:7873–7880
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
Saleh A, Srinivasula SM, Balkir L et al (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–483
Li C-Y, Lee J-S, Ko Y-G et al (2000) Heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation. J Biol Chem 275:25665–25671
Jäättelä M, Wissing D, Kokholm K et al (1998) Hsp70 exerts its anti‐apoptotic function downstream of caspase‐3‐like proteases. EMBO J 17(21):6124–6134. doi:10.1093/emboj/17.21.6124
Gyrd-Hansen M, Nylandsted J, Jäättelä M (2004) Heat shock protein 70 promotes cancer cell viability by safeguarding lysosomal integrity. Cell Cycle 3:1484–1485
Guicciardi ME, Leist M, Gores GJ (2004) Lysosomes in cell death. Oncogene 23:2881–2890
Hatfield MPD, Lovas S (2012) Role of Hsp70 in cancer growth and survival. Protein Pept Lett 19:616–624
Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918
Rohde M, Daugaard M, Jensen MH et al (2005) Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes Dev 19:570–582
Daugaard M, Jäättelä M, Rohde M (2005) Hsp70-2 is required for tumor cell growth and survival. Cell Cycle 4:877–880
Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323
Daugaard M, Kirkegaard-Sørensen T, Ostenfeld MS et al (2007) Lens epithelium-derived growth factor is an Hsp70-2 regulated guardian of lysosomal stability in human cancer. Cancer Res 67:2559–2567
Lee S-J, Lim H-S, Masliah E et al (2011) Protein aggregate spreading in neurodegenerative diseases: problems and perspectives. Neurosci Res 70:339–348
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909
Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403
Ross CA, Tabrizi SJ (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10:83–98
Hay DG, Sathasivam K, Tobaben S et al (2004) Progressive decrease in chaperone protein levels in a mouse model of Huntington’s disease and induction of stress proteins as a therapeutic approach. Hum Mol Genet 13:1389–1405
Iwasawa H, Kondo S, Ikeda D et al (1982) Synthesis of (-)-15-deoxyspergualin and (-)-spergualin-15-phosphate. J Antibiot (Tokyo) 35:1665–1669
Takeuchi T, Iinuma H, Kunimoto S et al (1981) A new antitumor antibiotic, spergualin: isolation and antitumor activity. J Antibiot (Tokyo) 34:1619–1621
Umezawa H, Kondo S, Iinuma H et al (1981) Structure of an antitumor antibiotic, spergualin. J Antibiot (Tokyo) 34:1622–1624
Umezawa H (1983) The Leeuwenhoek lecture, 1982: studies of microbial products in rising to the challenge of curing cancer. Proc R Soc Lond B Biol Sci 217:357–376
Holcombe H, Mellman I, Janeway CA et al (2002) The immunosuppressive agent 15-deoxyspergualin functions by inhibiting cell cycle progression and cytokine production following naive T cell activation. J Immunol 169:4982–4989
Muindi JF, Lee S-J, Baltzer L et al (1991) Clinical pharmacology of deoxyspergualin in patients with advanced cancer. Cancer Res 51:3096–3101
Bergeron RJ, McManis JS (1987) Total synthesis of (. + -.)-15-deoxyspergualin. J Org Chem 52:1700–1703
Maeda K, Umeda Y, Saino T (1993) Synthesis and background chemistry of 15-deoxyspergualin. Ann N Y Acad Sci 685:123–135
Evans CG, Smith MC, Carolan JP et al (2011) Improved synthesis of 15-deoxyspergualin analogs using the Ugi multi-component reaction. Bioorg Med Chem Lett 21:2587–2590
Umeda Y, Moriguchi M, Ikai K et al (1987) Synthesis and antitumor activity of spergualin analogues. III. Novel method for synthesis of optically active 15-deoxyspergualin and 15-deoxy-11-O-methylspergualin. J Antibiot (Tokyo) 40:1316–1324
Nadler SG, Tepper MA, Schacter B et al (1992) Interaction of the immunosuppressant deoxyspergualin with a member of the Hsp70 family of heat shock proteins. Science 258:484–486
Nadeau K, Nadler SG, Saulnier M et al (1994) Quantitation of the interaction of the immunosuppressant deoxyspergualin and analogs with Hsc70 and Hsp90. Biochemistry 33:2561–2567
Nadler SG, Dischino DD, Malacko AR et al (1998) Identification of a binding site on Hsc70 for the immunosuppressant 15-deoxyspergualin. Biochem Biophys Res Commun 253:176–180
Nosaka C, Kunimoto S, Takeuchi T (1999) The decrease of cytochrome c oxidase activity by 15-deoxyspergualin results in enhancement of XTT reduction in cultured cells. J Antibiot (Tokyo) 52:803
Hibasami H, Tsukada T, Suzuki R et al (1991) 15-Deoxyspergualin, an antiproliferative agent for human and mouse leukemia cells shows inhibitory effects on the synthetic pathway of polyamines. Anticancer Res 11:325–330
Tepper MA, Petty B, Bursuker I et al (1991) Inhibition of antibody production by the immunosuppressive agent, 15-deoxyspergualin. Transplant Proc 23:328–331
Ramya TN, Surolia N, Surolia A (2007) 15-deoxyspergualin inhibits eukaryotic protein synthesis through eIF2alpha phosphorylation. Biochem J 401:411–420
Banerjee T, Singh RR, Gupta S et al (2012) 15-Deoxyspergualin hinders physical interaction between basic residues of transit peptide in PfENR and Hsp70-1. IUBMB Life 64:99–107
Ohlman S, Zilg H, Schindel F et al (1994) Pharmacokinetics of 15-deoxyspergualin studied in renal transplant patients receiving the drug during graft rejection. Transpl Int 7:5–10
Kaufman DB, Gores PF, Kelley S et al (1996) 15-deoxyspergualin: immunotherapy in solid organ and cellular transplantation. Transplant Rev 10:160–174
Dhingra K, Valero V, Gutierrez L et al (1994) Phase II study of deoxyspergualin in metastatic breast cancer. Invest New Drugs 12:235–241
Lebreton L, Annat J, Derrepas P et al (1999) Structure − immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 1. Structural modifications of the hydroxyglycine moiety. J Med Chem 42:277–290
Lebreton L, Jost E, Carboni B et al (1999) Structure − immunosuppressive activity relationships of new analogues of 15-deoxyspergualin. 2. Structural modifications of the spermidine moiety. J Med Chem 42:4749–4763
Umeda Y, Moriguchi M, Kuroda H et al (1985) Synthesis and antitumor activity of spergualin analogues. I. Chemical modification of 7-guanidino-3-hydroxyacyl moiety. J Antibiot (Tokyo) 38:886–898
Umeda Y, Moriguchi M, Kuroda H et al (1987) Synthesis and antitumor activity of spergualin analogues. II. Chemical modification of the spermidine moiety. J Antibiot (Tokyo) 40:1303–1315
Fewell SW, Day BW, Brodsky JL (2001) Identification of an inhibitor of hsc70-mediated protein translocation and ATP hydrolysis. J Biol Chem 276:910–914
Fewell SW, Smith CM, Lyon MA et al (2004) Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. J Biol Chem 279:51131–51140
Werner S, Turner DM, Lyon MA et al (2006) A focused library of tetrahydropyrimidinone amides via a tandem Biginelli-Ugi multi-component process. Synlett 2006:2334–2338
Huryn DM, Resnick LO, Wipf P (2013) Contributions of academic laboratories to the discovery and development of chemical biology tools. J Med Chem. doi:10.1021/jm400132d
Wright CM, Seguin SP, Fewell SW et al (2009) Inhibition of Simian virus 40 replication by targeting the molecular chaperone function and ATPase activity of T antigen. Virus Res 141:71–80
Wright CM, Chovatiya RJ, Jameson NE et al (2008) Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation. Bioorg Med Chem 16:3291–3301
Jinwal UK, Miyata Y, Koren J 3rd et al (2009) Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci 29:12079–12088
Wisén S, Bertelsen EB, Thompson AD et al (2010) Binding of a small molecule at a protein–protein interface regulates the chaperone activity of Hsp70–Hsp40. ACS Chem Biol 5:611–622
Anna R, Yuhong S, Nian W et al (2007) Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer. Nat Chem Biol 3:498–507
Braunstein MJ, Scott SS, Scott CM et al (2011) Antimyeloma effects of the heat shock protein 70 molecular chaperone inhibitor MAL3-101. J Oncol. doi:10.1155/2011/232037:232037, 232011 pp
Ireland AW, Gobillot TA, Gupta T et al (2014) Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target. Bioorg Med Chem 22:6490–6502
Rabu C, Wipf P, Brodsky JL et al (2008) A precursor-specific role for Hsp40/Hsc70 during tail-anchored protein integration at the endoplasmic reticulum. J Biol Chem 283:27504–27513
Botha M, Chiang A, Needham P et al (2011) Plasmodium falciparum encodes a single cytosolic type I Hsp40 that functionally interacts with Hsp70 and is upregulated by heat shock. Cell Stress Chaperones 16:389–401
Chiang AN, Valderramos J-C, Balachandran R et al (2009) Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorg Med Chem 17:1527–1533
Lipinski CA, Lombardo F, Dominy BW et al (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26
Huryn DM, Brodsky JL, Brummond KM et al (2011) Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators. Proc Natl Acad Sci U S A 108:6757–6762
Wadhwa R, Sugihara T, Yoshida A et al (2000) Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function. Cancer Res 60:6818–6821
Tikoo A, Shakri R, Connolly L et al (2000) Treatment of ras-induced cancers by the F-actin-bundling drug MKT-077. Cancer J 6:162–168
Koya K, Li Y, Wang H et al (1996) MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation. Cancer Res 56:538–543
Propper DJ, Braybrooke JP, Taylor DJ et al (1999) Phase I trial of the selective mitochondrial toxin MKT077 in chemo-resistant solid tumours. Ann Oncol 10:923–927
Rousaki A, Miyata Y, Jinwal UK et al (2011) Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. J Mol Biol 411:614–632
Li X, Srinivasan SR, Connarn J et al (2013) Analogues of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents. ACS Med Chem Lett 4:1042–1047
Whetstone H, Lingwood C (2003) 3′Sulfogalactolipid binding specifically inhibits Hsp70 ATPase activity in vitro. Biochemistry 42:1611–1617
Boulanger J, Faulds D, Eddy EM et al (1995) Members of the 70 kDa heat shock protein family specifically recognize sulfoglycolipids: role in gamete recognition and mycoplasma-related infertility. J Cell Physiol 165:7–17
Mamelak D, Lingood C (1997) Expression and sulfogalactolipid binding specificity of the recombinant testis-specific cognate heat shock protein 70. Glycoconj J 14:715–722
Mamelak D, Mylvaganam M, Whetstone H et al (2001) Hsp70s contain a specific sulfogalactolipid binding site. Differential aglycone influence on sulfogalactosyl ceramide binding by recombinant prokaryotic and eukaryotic Hsp70 family members. Biochemistry 40:3572–3582
Mamelak D, Lingwood C (2001) The ATPase domain of hsp70 possesses a unique binding specificity for 3′-sulfogalactolipids. J Biol Chem 276:449–456
Mamelak D, Mylvaganam M, Tanahashi E et al (2001) The aglycone of sulfogalactolipids can alter the sulfate ester substitution position required for hsc70 recognition. Carbohydr Res 335:91–100
Park H-J, Mylvaganum M, McPherson A et al (2009) A soluble sulfogalactosyl ceramide mimic promotes ΔF508 CFTR escape from endoplasmic reticulum associated degradation. Chem Biol 16:461–470
De Rosa M, Park HJ, Mylvaganum M et al (2008) The medium is the message: glycosphingolipids and their soluble analogues. BBA Gen Sub 1780:347–352
Schmitt E, Parcellier A, Gurbuxani S et al (2003) Chemosensitization by a non-apoptogenic heat shock protein 70-binding apoptosis-inducing factor mutant. Cancer Res 63:8233–8240
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
Schmitt E, Maingret L, Puig P-E et al (2006) Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma. Cancer Res 66:4191–4197
Chalmin F, Ladoire S, Mignot G et al (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471
Rérole A-L, Gobbo J, De Thonel A et al (2011) Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy. Cancer Res 71:484–495
Jego G, Hazoumé A, Seigneuric R et al (2013) Targeting heat shock proteins in cancer. Cancer Lett 332:275–285
Williams DR, Ko S-K, Park S et al (2008) An apoptosis-inducing small molecule that binds to heat shock protein 70. Angew Chem Int Ed 47:7466–7469
Shin I-j, Lee M-r, Williams D (2010) Imidazole derivatives that induce apoptosis and their therapeutic uses. United States Patent
Lev N, Melamed E, Offen D (2003) Apoptosis and Parkinson’s disease. Prog Neuropsychopharmacol 27:245–250
Behl C (2000) Apoptosis and Alzheimer’s disease. J Neural Transm 107:1325–1344
Meacham GC, Lu Z, King S et al (1999) The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis. EMBO J 18:1492–1505
Zhang Y, Nijbroek G, Sullivan ML et al (2001) Hsp70 molecular chaperone facilitates endoplasmic reticulum-associated protein degradation of cystic fibrosis transmembrane conductance regulator in yeast. Mol Biol Cell 12:1303–1314
Williamson DS, Borgognoni J, Clay A et al (2009) Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design. J Med Chem 52:1510–1513
Macias AT, Williamson DS, Allen N et al (2011) Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity. J Med Chem 54:4034–4041
Dong D, Ni M, Li J et al (2008) Critical role of the stress chaperone GRP78/BiP in tumor proliferation, survival, and tumor angiogenesis in transgene-induced mammary tumor development. Cancer Res 68:498–505
Li J, Lee AS (2006) Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 6:45–54
Massey AJ, Dopson M, Lavan P et al (2010) A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 66:535–545
Chatterjee M, Andrulis M, Stuhmer T et al (2012) The PI3K/Akt signalling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma. Haematologica. doi:10.3324/haematol.2012.066175
Reikvam H, Nepstad I, Sulen A et al (2013) Increased antileukemic effects in human acute myeloid leukemia by combining HSP70 and HSP90 inhibitors. Expert Opin Invest Drugs 22:551–563
Strom E, Sathe S, Komarov PG et al (2006) Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation. Nat Chem Biol 2:474–479
Leu JI-J, George DL (2007) Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria. Genes Dev 21:3095–3109
Leu JIJ, Pimkina J, Frank A et al (2009) A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 36:15–27
Liu EY, Ryan KM (2012) Autophagy and cancer–issues we need to digest. J Cell Sci 125:2349–2358
Balaburski GM, Leu JI, Beeharry N et al (2013) A modified HSP70 inhibitor shows broad activity as an anticancer agent. Mol Cancer Res 11:219–229
Leu JI-J, Pimkina J, Pandey P et al (2011) HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells. Mol Cancer Res 9:936–947
Kaiser M, Kuhnl A, Reins J et al (2011) Antileukemic activity of the HSP70 inhibitor pifithrin-mu in acute leukemia. Blood Cancer J 1:e28
Pimkina JS, Murphy ME (2011) Interaction of the ARF tumor suppressor with cytosolic HSP70 contributes to its autophagy function. Cancer Biol Ther 12:503–509
Budina-Kolomets A, Balaburski GM, Bondar A et al (2014) Comparison of the activity of three different HSP70 inhibitors on apoptosis, cell cycle arrest, autophagy inhibition, and HSP90 inhibition. Cancer Biol Ther 15:194–199
Jinwal UK, Koren J, O’Leary JC et al (2010) Hsp70 ATPase modulators as therapeutics for Alzheimer’s and other neurodegenerative diseases. Mol Cell Pharmacol 2:43–46
Koren J, Jinwal UK, Jin Y et al (2010) Facilitating Akt clearance via manipulation of Hsp70 activity and levels. J Biol Chem 285:2498–2505
Chang L, Miyata Y, Ung PMU et al (2011) Chemical screens against a reconstituted multiprotein complex: myricetin blocks DnaJ regulation of DnaK through an allosteric mechanism. Chem Biol 18:210–221
Medina DX, Caccamo A, Oddo S (2011) Methylene blue reduces Aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol 21:140–149
Rodina A, Patel Pallav D, Kang Y et al (2013) Identification of an allosteric pocket on human Hsp70 reveals a mode of inhibition of this therapeutically important protein. Chem Biol 20:1469–1480
Kang Y, Taldone T, Patel HJ et al (2014) Heat shock protein 70 inhibitors. 1. 2,5′-thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides as irreversible binders to an allosteric site on heat shock protein 70. J Med Chem 57:1188–1207
Taldone T, Kang Y, Patel HJ et al (2014) Heat shock protein 70 inhibitors. 2. 2,5′-thiodipyrimidines, 5-(phenylthio)pyrimidines, 2-(pyridin-3-ylthio)pyrimidines, and 3-(phenylthio)pyridines as reversible binders to an allosteric site on heat shock protein 70. J Med Chem 57:1208–1224
Howe Matthew K, Bodoor K, Carlson David A et al (2014) Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70. Chem Biol 21:1648–1659
Hassan AQ, Kirby Christina A, Zhou W et al (2015) The novolactone natural product disrupts the allosteric regulation of Hsp70. Chem Biol 22:87–97
Ciocca DR, Arrigo AP, Calderwood SK (2013) Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol 87:19–48
Heimberger T, Andrulis M, Riedel S et al (2013) The heat shock transcription factor 1 as a potential new therapeutic target in multiple myeloma. Br J Haematol 160:465–476
Kieran D, Kalmar B, Dick JR et al (2004) Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 10:402–405
Lanka V, Wieland S, Barber J et al (2009) Arimoclomol: a potential therapy under development for ALS. Expert Opin Invest Drugs 18:1907–1918
Hosokawa N, Hirayoshi K, Nakai A et al (1990) Flavonoids inhibit the expression of heat shock proteins. Cell Struct Funct 15:393–401
Koishi M, Hosokawa N, Sato M et al (1992) Quercetin, an inhibitor of heat shock protein synthesis, inhibits the acquisition of thermotolerance in a human colon carcinoma cell line. Jpn J Cancer Res 83:1216–1222
Hosokawa N, Hirayoshi K, Kudo H et al (1992) Inhibition of the activation of heat shock factor in vivo and in vitro by flavonoids. Mol Cell Biol 12:3490–3498
Elia G, Amici C, Rossi A et al (1996) Modulation of prostaglandin A1-induced thermotolerance by quercetin in human leukemic cells: role of heat shock protein 70. Cancer Res 56:210–217
Hansen RK, Oesterreich S, Lemieux P et al (1997) Quercetin inhibits heat shock protein induction but not heat shock factor DNA-binding in human breast carcinoma cells. Biochem Biophys Res Commun 239:851–856
Suolinna EM, Buchsbaum RN, Racker E (1975) The effect of flavonoids on aerobic glycolysis and growth of tumor cells. Cancer Res 35:1865–1872
Graziani Y, Chayoth R, Karny N et al (1982) Regulation of protein kinases activity by quercetin in Ehrlich ascites tumor cells. Biochim Biophys Acta 714:415–421
Wiseman RL, Zhang Y, Lee KPK et al (2010) Flavonol activation defines an unanticipated ligand-binding site in the kinase-RNase domain of IRE1. Mol Cell 38:291–304
Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4:966–977
Boulton DW, Walle UK, Walle T (1999) Fate of the flavonoid quercetin in human cell lines: chemical instability and metabolism. J Pharm Pharmacol 51:353–359
Manwell LA, Heikkila JJ (2007) Examination of KNK437- and quercetin-mediated inhibition of heat shock-induced heat shock protein gene expression in Xenopus laevis cultured cells. Comp Biochem Physiol A Mol Integr Physiol 148:521–530
Yokota S-i, Kitahara M, Nagata K (2000) Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells. Cancer Res 60:2942–2948
Koishi M, Yokota S, Mae T et al (2001) The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo. Clin Cancer Res 7:215–219
Ohnishi K, Takahashi A, Yokota S et al (2004) Effects of a heat shock protein inhibitor KNK437 on heat sensitivity and heat tolerance in human squamous cell carcinoma cell lines differing in p53 status. Int J Radiat Biol 80:607–614
Qiu D, Kao PN (2003) Immunosuppressive and anti-inflammatory mechanisms of triptolide, the principal active diterpenoid from the Chinese medicinal herb Tripterygium wilfordii Hook. f. Drugs R D 4:1–18
Westerheide SD, Kawahara TLA, Orton K et al (2006) Triptolide, an inhibitor of the human heat shock response that enhances stress-induced cell death. J Biol Chem 281:9616–9622
Phillips PA, Dudeja V, McCarroll JA et al (2007) Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res 67:9407–9416
Antonoff MB, Chugh R, Skube SJ et al (2010) Role of Hsp-70 in triptolide-mediated cell death of neuroblastoma. J Surg Res 163:72–78
Kizelsztein P, Komarnytsky S, Raskin I (2009) Oral administration of triptolide ameliorates the clinical signs of experimental autoimmune encephalomyelitis (EAE) by induction of HSP70 and stabilization of NF-κB/IκBα transcriptional complex. J Neuroimmunol 217:28–37
Xia Y, Liu Y, Rocchi P et al (2012) Targeting heat shock factor 1 with a triazole nucleoside analog to elicit potent anticancer activity on drug-resistant pancreatic cancer. Cancer Lett 318:145–153
Xia Y, Liu Y, Wan J et al (2009) Novel triazole ribonucleoside down-regulates heat shock protein 27 and induces potent anticancer activity on drug-resistant pancreatic cancer. J Med Chem 52:6083–6096
Mendillo Marc L, 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
van der Putten H, Lotz G (2013) Opportunities and challenges for molecular chaperone modulation to treat protein-conformational brain diseases. Neurotherapeutics 10:416–428
Acknowledgments
This project was supported with federal funds from the National Institute of General Medical Sciences (GM75061, P30 DK79307, and P50 GM067082) and an American Australian Association Merck Company Foundation Fellowship (AM-T).
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Manos-Turvey, A., Brodsky, J.L., Wipf, P. (2015). The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics. 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_90
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