The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

  • Alexandra Manos-Turvey
  • Jeffrey L. Brodsky
  • Peter Wipf
Part of the Topics in Medicinal Chemistry book series (TMC, volume 19)


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.


15-Deoxyspergualin ADD70 Apoptozole Hsc70 Hsp70 MAL3-101 VER-155008 



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).


  1. 1.
    Ensembl (2013) Human assembly and gene annotation. Accessed 20 Feb 2013
  2. 2.
    Flicek P, Amode MR, Barrell D et al (2012) Ensembl 2012. Nucleic Acids Res 40:D84–D90CrossRefGoogle Scholar
  3. 3.
    Walsh CT, Garneau-Tsodikova S, Gatto GJ (2005) Protein posttranslational modifications: the chemistry of proteome diversifications. Angew Chem Int Ed 44:7342–7372CrossRefGoogle Scholar
  4. 4.
    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 12:1–5CrossRefGoogle Scholar
  5. 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
  6. 6.
    Chaudhuri TK, Paul S (2006) Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J 273:1331–1349CrossRefGoogle Scholar
  7. 7.
    Rutkowski DT, Hegde RS (2010) Regulation of basal cellular physiology by the homeostatic unfolded protein response. J Cell Biol 189:783–794CrossRefGoogle Scholar
  8. 8.
    Ellis J (1987) Proteins as molecular chaperones. Nature 328:378–379CrossRefGoogle Scholar
  9. 9.
    Lee AS (1987) Coordinated regulation of a set of genes by glucose and calcium ionophores in mammalian cells. Trends Biochem Sci 12:20–23CrossRefGoogle Scholar
  10. 10.
    Frydman J (2001) Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem 70:603CrossRefGoogle Scholar
  11. 11.
    Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858CrossRefGoogle Scholar
  12. 12.
    McClellan AJ, Frydman J (2001) Molecular chaperones and the art of recognizing a lost cause. Nat Cell Biol 3:E51CrossRefGoogle Scholar
  13. 13.
    Jolly C, Morimoto RI (2000) Role of the heat shock response and molecular chaperones in oncogenesis and cell death. J Natl Cancer Inst 92:1564–1572CrossRefGoogle Scholar
  14. 14.
    Pelham HRB (1986) Speculations on the functions of the major heat shock and glucose-regulated proteins. Cell 46:959–961CrossRefGoogle Scholar
  15. 15.
    Yao T-P (2010) The role of ubiquitin in autophagy-dependent protein aggregate processing. Genes Cancer 1:779–786CrossRefGoogle Scholar
  16. 16.
    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 89:1175–1182CrossRefGoogle Scholar
  17. 17.
    Kaushik S, Bandyopadhyay U, Sridhar S et al (2011) Chaperone-mediated autophagy at a glance. J Cell Sci 124:495–499CrossRefGoogle Scholar
  18. 18.
    Powers MV, Workman P (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581:3758–3769CrossRefGoogle Scholar
  19. 19.
    Calderwood SK, Stevenson MA, Murshid A (2012) Heat shock proteins, autoimmunity, and cancer treatment. Autoimmune Dis 2012:10Google Scholar
  20. 20.
    Murphy ME (2013) The HSP70 family and cancer. Carcinogenesis 34:1181–1188CrossRefGoogle Scholar
  21. 21.
    Sherman MY, Gabai VL (2014) Hsp70 in cancer: back to the future. Oncogene. doi: 10.1038/onc.2014.349 Google Scholar
  22. 22.
    Massey AJ (2010) ATPases as drug targets: insights from heat shock proteins 70 and 90. J Med Chem 53:7280–7286CrossRefGoogle Scholar
  23. 23.
    Yamaki H, Nakajima M, Shimotohno KW et al (2011) Molecular basis for the actions of Hsp90 inhibitors and cancer therapy. J Antibiot (Tokyo) 64:635–644CrossRefGoogle Scholar
  24. 24.
    Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772CrossRefGoogle Scholar
  25. 25.
    Neckers L (2007) Heat shock protein 90: the cancer chaperone. J Biosci 32:517–530CrossRefGoogle Scholar
  26. 26.
    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 6:559–587CrossRefGoogle Scholar
  27. 27.
    Zhang H, Burrows F (2004) Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med 82:488–499Google Scholar
  28. 28.
    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 33–44CrossRefGoogle Scholar
  29. 29.
    Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–294CrossRefGoogle Scholar
  30. 30.
    DeBoer C, Meulman PA, Wnuk RJ et al (1970) Geldanamycin, a new antibiotic. J Antibiot (Tokyo) 23:442–447CrossRefGoogle Scholar
  31. 31.
    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 89:239–250CrossRefGoogle Scholar
  32. 32.
    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 91:8324–8328CrossRefGoogle Scholar
  33. 33.
    Den RB, Lu B (2012) Heat shock protein 90 inhibition: rationale and clinical potential. Ther Adv Med Oncol 4:211–218CrossRefGoogle Scholar
  34. 34.
    Whitesell L, Lin NU (2012) HSP90 as a platform for the assembly of more effective cancer chemotherapy. BBA Mol Cell Res 1823:756–766Google Scholar
  35. 35.
    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 63:2139–2144Google Scholar
  36. 36.
    Kamal A, Thao L, Sensintaffar J et al (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425:407–410CrossRefGoogle Scholar
  37. 37.
    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 26:7185–7193CrossRefGoogle Scholar
  38. 38.
    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 11:1466–1476Google Scholar
  39. 39.
    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 51:196–218CrossRefGoogle Scholar
  40. 40.
    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 68:2850–2860CrossRefGoogle Scholar
  41. 41.
    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 12:890–900CrossRefGoogle Scholar
  42. 42.
    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:e0001722CrossRefGoogle Scholar
  43. 43.
    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 17:1561–1570CrossRefGoogle Scholar
  44. 44.
    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 65:10536–10544CrossRefGoogle Scholar
  45. 45.
    Cui XB, Yu ZY, Wang W et al (2012) Co-inhibition of HSP70/HSP90 synergistically sensitizes nasopharyngeal carcinoma cells to thermotherapy. Integr Cancer Ther 11:61–67CrossRefGoogle Scholar
  46. 46.
    Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124CrossRefGoogle Scholar
  47. 47.
    Brodsky JL, Chiosis G (2006) Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulators. Curr Top Med Chem 6:1215–1225CrossRefGoogle Scholar
  48. 48.
    Buck TM, Wright CM, Brodsky JL (2007) The activities and function of molecular chaperones in the endoplasmic reticulum. Semin Cell Dev Biol 18:751–761CrossRefGoogle Scholar
  49. 49.
    Bukau B, Weissman J, Horwich A (2006) Molecular chaperones and protein quality control. Cell 125:443–451CrossRefGoogle Scholar
  50. 50.
    Fewell SW, Travers KJ, Weissman JS et al (2001) The action of molecular chaperones in the early secretory pathway. Annu Rev Genet 35:149–191CrossRefGoogle Scholar
  51. 51.
    Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670–684CrossRefGoogle Scholar
  52. 52.
    Massey AC, Zhang C, Cuervo AM (2006) Chaperone-mediated autophagy in aging and disease. Curr Top Dev Biol 73:205–235CrossRefGoogle Scholar
  53. 53.
    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 281:33182–33191CrossRefGoogle Scholar
  54. 54.
    Kirkegaard T, Roth AG, Petersen NH et al (2010) Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature 463:549–553CrossRefGoogle Scholar
  55. 55.
    Brodsky JL (2001) Chaperoning the maturation of the cystic fibrosis transmembrane conductance regulator. Am J Physiol Lung Cell Mol Physiol 281:L39–L42Google Scholar
  56. 56.
    Turturici G, Sconzo G, Geraci F (2011) Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. doi: 10.1155/2011/618127 Google Scholar
  57. 57.
    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 Google Scholar
  58. 58.
    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 97:9701–9705CrossRefGoogle Scholar
  59. 59.
    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 9:2009–2018CrossRefGoogle Scholar
  60. 60.
    Witt SN (2010) Hsp70 molecular chaperones and Parkinson’s disease. Biopolymers 93:218–228CrossRefGoogle Scholar
  61. 61.
    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 133:20267–20276CrossRefGoogle Scholar
  62. 62.
    Boorstein WR, Ziegelhoffer T, Craig EA (1994) Molecular evolution of the HSP70 multigene family. J Mol Evol 38:1–17CrossRefGoogle Scholar
  63. 63.
    Rensing SA, Maier UG (1994) Phylogenetic analysis of the stress-70 protein family. J Mol Evol 39:80–86CrossRefGoogle Scholar
  64. 64.
    Daugaard M, Rohde M, Jäättelä M (2007) The heat shock protein 70 family: highly homologous proteins with overlapping and distinct functions. FEBS Lett 581:3702–3710CrossRefGoogle Scholar
  65. 65.
    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 82:6455–6459CrossRefGoogle Scholar
  66. 66.
    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 81:848–852CrossRefGoogle Scholar
  67. 67.
    Flaherty KM, DeLuca-Flaherty C, McKay DB (1990) Three-dimensional structure of the ATPase fragment of a 70k heat-shock cognate protein. Nature 346:623–628CrossRefGoogle Scholar
  68. 68.
    Normington K, Kohno K, Kozutsumi Y et al (1989) S. cerevisiae encodes an essential protein homologous in sequence and function to mammalian BiP. Cell 57:1223–1236CrossRefGoogle Scholar
  69. 69.
    Zhu X, Zhao X, Furkholder WF et al (1996) Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272:1606–1614CrossRefGoogle Scholar
  70. 70.
    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 14:2281–2292Google Scholar
  71. 71.
    Allan RK, Ratajczak T (2011) Versatile TPR domains accommodate different modes of target protein recognition and function. Cell Stress Chaperones 16:353–367CrossRefGoogle Scholar
  72. 72.
    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 101:199–210CrossRefGoogle Scholar
  73. 73.
    Zhuravleva A, Clerico EM, Gierasch LM (2012) An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell 151:1296–1307CrossRefGoogle Scholar
  74. 74.
    Cyr DM (2008) Swapping nucleotides, tuning Hsp70. Cell 133:945–947CrossRefGoogle Scholar
  75. 75.
    Kityk R, Kopp J, Sinning I et al (2012) Structure and dynamics of the ATP-bound open conformation of Hsp70 chaperones. Mol Cell 48:863–874CrossRefGoogle Scholar
  76. 76.
    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 26:27–39CrossRefGoogle Scholar
  77. 77.
    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 101:10272–10277CrossRefGoogle Scholar
  78. 78.
    Pellecchia M, Montgomery DL, Stevens SY et al (2000) Structural insights into substrate binding by the molecular chaperone DnaK. Nat Struct Biol 7:298–303CrossRefGoogle Scholar
  79. 79.
    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 41:12224–12235CrossRefGoogle Scholar
  80. 80.
    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 20:900–907CrossRefGoogle Scholar
  81. 81.
    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 106:8471–8476CrossRefGoogle Scholar
  82. 82.
    Kelley WL (1998) The J-domain family and the recruitment of chaperone power. Trends Biochem Sci 23:222–227CrossRefGoogle Scholar
  83. 83.
    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 96:5452–5457CrossRefGoogle Scholar
  84. 84.
    Jiang J, Maes EG, Taylor AB et al (2007) Structural basis of J cochaperone binding and regulation of Hsp70. Mol Cell 28:422–433CrossRefGoogle Scholar
  85. 85.
    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 95:15223–15228CrossRefGoogle Scholar
  86. 86.
    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 95:15229–15234CrossRefGoogle Scholar
  87. 87.
    Kampinga HH, Craig EA (2010) The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat Rev Mol Cell Biol 11:579–592CrossRefGoogle Scholar
  88. 88.
    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 106:11073–11078CrossRefGoogle Scholar
  89. 89.
    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 CrossRefGoogle Scholar
  90. 90.
    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 12:4137–4144Google Scholar
  91. 91.
    Polier S, Dragovic Z, Hartl FU et al (2008) Structural basis for the cooperation of Hsp70 and Hsp110 chaperones in protein folding. Cell 133:1068–1079CrossRefGoogle Scholar
  92. 92.
    Tzankov S, Wong MJH, Shi K et al (2008) Functional divergence between co-chaperones of Hsc70. J Biol Chem 283:27100–27109CrossRefGoogle Scholar
  93. 93.
    Shaner L, Morano KA (2007) All in the family: atypical Hsp70 chaperones are conserved modulators of Hsp70 activity. Cell Stress Chaperones 12:1–8CrossRefGoogle Scholar
  94. 94.
    Schuermann JP, Jiang J, Cuellar J et al (2008) Structure of the Hsp110:Hsc70 nucleotide exchange machine. Mol Cell 31:232–243CrossRefGoogle Scholar
  95. 95.
    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 8:19CrossRefGoogle Scholar
  96. 96.
    Wu B, Hunt C, Morimoto R (1985) Structure and expression of the human gene encoding major heat shock protein HSP70. Mol Cell Biol 5:330–341CrossRefGoogle Scholar
  97. 97.
    Tavaria M, Gabriele T, Kola I et al (1996) A hitchhiker’s guide to the human Hsp70 family. Cell Stress Chaperones 1:23–28CrossRefGoogle Scholar
  98. 98.
    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 14:1–21CrossRefGoogle Scholar
  99. 99.
    Wu C (1995) Heat shock transcription factors: structure and regulation. Annu Rev Cell Dev Biol 11:441–469CrossRefGoogle Scholar
  100. 100.
    Calderwood SK, Xie Y, Wang X et al (2010) Signal transduction pathways leading to heat shock transcription. Sign Transduct Insights 2:13–24CrossRefGoogle Scholar
  101. 101.
    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 24:899–911CrossRefGoogle Scholar
  102. 102.
    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 171:2680–2688Google Scholar
  103. 103.
    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 7:2568–2577CrossRefGoogle Scholar
  104. 104.
    Calloni G, Chen T, Schermann Sonya M et al (2012) DnaK functions as a central hub in the E. coli chaperone network. Cell Rep 1:251–264CrossRefGoogle Scholar
  105. 105.
    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 267:125–132CrossRefGoogle Scholar
  106. 106.
    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 1494:201–205CrossRefGoogle Scholar
  107. 107.
    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 101:6062–6067CrossRefGoogle Scholar
  108. 108.
    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 136:354–374CrossRefGoogle Scholar
  109. 109.
    Dworniczak B, Mirault ME (1987) Structure and expression of a human gene coding for a 71 kd heat shock ‘cognate’ protein. Nucleic Acids Res 15:5181–5197CrossRefGoogle Scholar
  110. 110.
    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 21:8575–8591CrossRefGoogle Scholar
  111. 111.
    Florin L, Becker KA, Sapp C et al (2004) Nuclear translocation of papillomavirus minor capsid protein L2 requires Hsc70. J Virol 78:5546–5553CrossRefGoogle Scholar
  112. 112.
    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 23:85–93CrossRefGoogle Scholar
  113. 113.
    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 93:3264–3268CrossRefGoogle Scholar
  114. 114.
    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 46:291–300CrossRefGoogle Scholar
  115. 115.
    Munro S, Pelham HRB (1987) A C-terminal signal prevents secretion of luminal ER proteins. Cell 48:899–907CrossRefGoogle Scholar
  116. 116.
    Haas IG (1994) BiP (GRP78), an essential hsp70 resident protein in the endoplasmic reticulum. Experientia 50:1012–1020CrossRefGoogle Scholar
  117. 117.
    Consortium TU (2012) Reorganizing the protein space at the Universal Protein Resource (UniProt). Nucleic Acids Res 40:D71–D75CrossRefGoogle Scholar
  118. 118.
    Bhattacharyya T, Karnezis AN, Murphy SP et al (1995) Cloning and subcellular localization of human mitochondrial hsp70. J Biol Chem 270:1705–1710CrossRefGoogle Scholar
  119. 119.
    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 264:20664–20675Google Scholar
  120. 120.
    Deocaris CC, Kaul SC, Wadhwa R (2006) On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60. Cell Stress Chaperones 11:116–128CrossRefGoogle Scholar
  121. 121.
    Omura T (1998) Mitochondria-targeting sequence, a multi-role sorting sequence recognized at all steps of protein import into mitochondria. J Biochem 123:1010–1016CrossRefGoogle Scholar
  122. 122.
    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 9:3000–3008CrossRefGoogle Scholar
  123. 123.
    Bukau B, Deuerling E, Pfund C et al (2000) Getting newly synthesized proteins into shape. Cell 101:119–122CrossRefGoogle Scholar
  124. 124.
    Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332CrossRefGoogle Scholar
  125. 125.
    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 107:9111–9116CrossRefGoogle Scholar
  126. 126.
    Elcock AH (2006) Molecular simulations of cotranslational protein folding: fragment stabilities, folding cooperativity, and trapping in the ribosome. PLoS Comput Biol 2:e98CrossRefGoogle Scholar
  127. 127.
    Slepenkov SV, Witt SN (2002) The unfolding story of the Escherichia coli Hsp70 DnaK: is DnaK a holdase or an unfoldase? Mol Microbiol 45:1197–1206CrossRefGoogle Scholar
  128. 128.
    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 273:5970–5978CrossRefGoogle Scholar
  129. 129.
    Yan W, Schilke B, Pfund C et al (1998) Zuotin, a ribosome-associated DnaJ molecular chaperone. EMBO J 17:4809–4817CrossRefGoogle Scholar
  130. 130.
    Höhfeld J, Minami Y, Hartl F-U (1995) Hip, a novel cochaperone involved in the eukaryotic hsc70/hsp40 reaction cycle. Cell 83:589–598CrossRefGoogle Scholar
  131. 131.
    Hohfeld J, Jentsch S (1997) GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1. EMBO J 16:6209–6216CrossRefGoogle Scholar
  132. 132.
    Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92:351–366CrossRefGoogle Scholar
  133. 133.
    Sigler PB, Xu Z, Rye HS et al (1998) Structure and function in GroEL-mediated protein-folding. Annu Rev Biochem 67:581CrossRefGoogle Scholar
  134. 134.
    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 15:858–864CrossRefGoogle Scholar
  135. 135.
    Rosenzweig R, Moradi S, Zarrine-Afsar A et al (2013) Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction. Science 339:1080–1083CrossRefGoogle Scholar
  136. 136.
    Glover JR, Lindquist S (1998) Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94:73–82CrossRefGoogle Scholar
  137. 137.
    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 19:1347–1355CrossRefGoogle Scholar
  138. 138.
    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 96:13732–13737CrossRefGoogle Scholar
  139. 139.
    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 279:37298–37303CrossRefGoogle Scholar
  140. 140.
    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 275:21107–21113CrossRefGoogle Scholar
  141. 141.
    Rampelt H, Kirstein-Miles J, Nillegoda NB et al (2012) Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. EMBO J 31:4221CrossRefGoogle Scholar
  142. 142.
    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 12:2186–2192CrossRefGoogle Scholar
  143. 143.
    Pratt WB, Toft DO (1997) Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev 18:306–360Google Scholar
  144. 144.
    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 Google Scholar
  145. 145.
    Hernández MP, Sullivan WP, Toft DO (2002) The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone complex. J Biol Chem 277:38294–38304CrossRefGoogle Scholar
  146. 146.
    Pratt WB, Toft DO (2003) Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med 228:111–133Google Scholar
  147. 147.
    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 267:9202–9209Google Scholar
  148. 148.
    McDonough H, Patterson C (2003) CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 8:303–308CrossRefGoogle Scholar
  149. 149.
    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 19:4535–4545CrossRefGoogle Scholar
  150. 150.
    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 276:42938–42944CrossRefGoogle Scholar
  151. 151.
    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 11:1569–1577CrossRefGoogle Scholar
  152. 152.
    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 275:4613–4617CrossRefGoogle Scholar
  153. 153.
    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 20:7146–7159CrossRefGoogle Scholar
  154. 154.
    Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (Hsp70) as an emerging drug target. J Med Chem 53:4585–4602CrossRefGoogle Scholar
  155. 155.
    Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516CrossRefGoogle Scholar
  156. 156.
    Salomoni P, Khelifi AF (2006) Daxx: death or survival protein? Trends Cell Biol 16:97–104CrossRefGoogle Scholar
  157. 157.
    Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27:6245–6251CrossRefGoogle Scholar
  158. 158.
    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 7:1166–1173CrossRefGoogle Scholar
  159. 159.
    Schmitt E, Gehrmann M, Brunet M et al (2007) Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol 81:15–27CrossRefGoogle Scholar
  160. 160.
    Zorzi E, Bonvini P (2011) Inducible Hsp70 in the regulation of cancer cell survival: analysis of chaperone induction, expression and activity. Cancer 3:3921–3956CrossRefGoogle Scholar
  161. 161.
    Stankiewicz AR, Lachapelle G, Foo CPZ et al (2005) Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 280:38729–38739CrossRefGoogle Scholar
  162. 162.
    Ruchalski K, Mao H, Li Z et al (2006) Distinct hsp70 domains mediate apoptosis-inducing factor release and nuclear accumulation. J Biol Chem 281:7873–7880CrossRefGoogle Scholar
  163. 163.
    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 2:469–475CrossRefGoogle Scholar
  164. 164.
    Saleh A, Srinivasula SM, Balkir L et al (2000) Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol 2:476–483CrossRefGoogle Scholar
  165. 165.
    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 275:25665–25671CrossRefGoogle Scholar
  166. 166.
    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 CrossRefGoogle Scholar
  167. 167.
    Gyrd-Hansen M, Nylandsted J, Jäättelä M (2004) Heat shock protein 70 promotes cancer cell viability by safeguarding lysosomal integrity. Cell Cycle 3:1484–1485CrossRefGoogle Scholar
  168. 168.
    Guicciardi ME, Leist M, Gores GJ (2004) Lysosomes in cell death. Oncogene 23:2881–2890CrossRefGoogle Scholar
  169. 169.
    Hatfield MPD, Lovas S (2012) Role of Hsp70 in cancer growth and survival. Protein Pept Lett 19:616–624CrossRefGoogle Scholar
  170. 170.
    Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918CrossRefGoogle Scholar
  171. 171.
    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 19:570–582CrossRefGoogle Scholar
  172. 172.
    Daugaard M, Jäättelä M, Rohde M (2005) Hsp70-2 is required for tumor cell growth and survival. Cell Cycle 4:877–880CrossRefGoogle Scholar
  173. 173.
    Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323CrossRefGoogle Scholar
  174. 174.
    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 67:2559–2567CrossRefGoogle Scholar
  175. 175.
    Lee S-J, Lim H-S, Masliah E et al (2011) Protein aggregate spreading in neurodegenerative diseases: problems and perspectives. Neurosci Res 70:339–348CrossRefGoogle Scholar
  176. 176.
    Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909CrossRefGoogle Scholar
  177. 177.
    Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403CrossRefGoogle Scholar
  178. 178.
    Ross CA, Tabrizi SJ (2011) Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 10:83–98CrossRefGoogle Scholar
  179. 179.
    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 13:1389–1405CrossRefGoogle Scholar
  180. 180.
    Iwasawa H, Kondo S, Ikeda D et al (1982) Synthesis of (-)-15-deoxyspergualin and (-)-spergualin-15-phosphate. J Antibiot (Tokyo) 35:1665–1669CrossRefGoogle Scholar
  181. 181.
    Takeuchi T, Iinuma H, Kunimoto S et al (1981) A new antitumor antibiotic, spergualin: isolation and antitumor activity. J Antibiot (Tokyo) 34:1619–1621CrossRefGoogle Scholar
  182. 182.
    Umezawa H, Kondo S, Iinuma H et al (1981) Structure of an antitumor antibiotic, spergualin. J Antibiot (Tokyo) 34:1622–1624CrossRefGoogle Scholar
  183. 183.
    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 217:357–376CrossRefGoogle Scholar
  184. 184.
    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 169:4982–4989CrossRefGoogle Scholar
  185. 185.
    Muindi JF, Lee S-J, Baltzer L et al (1991) Clinical pharmacology of deoxyspergualin in patients with advanced cancer. Cancer Res 51:3096–3101Google Scholar
  186. 186.
    Bergeron RJ, McManis JS (1987) Total synthesis of (. + -.)-15-deoxyspergualin. J Org Chem 52:1700–1703CrossRefGoogle Scholar
  187. 187.
    Maeda K, Umeda Y, Saino T (1993) Synthesis and background chemistry of 15-deoxyspergualin. Ann N Y Acad Sci 685:123–135CrossRefGoogle Scholar
  188. 188.
    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 21:2587–2590CrossRefGoogle Scholar
  189. 189.
    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) 40:1316–1324CrossRefGoogle Scholar
  190. 190.
    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 258:484–486CrossRefGoogle Scholar
  191. 191.
    Nadeau K, Nadler SG, Saulnier M et al (1994) Quantitation of the interaction of the immunosuppressant deoxyspergualin and analogs with Hsc70 and Hsp90. Biochemistry 33:2561–2567CrossRefGoogle Scholar
  192. 192.
    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 253:176–180CrossRefGoogle Scholar
  193. 193.
    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) 52:803CrossRefGoogle Scholar
  194. 194.
    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 11:325–330Google Scholar
  195. 195.
    Tepper MA, Petty B, Bursuker I et al (1991) Inhibition of antibody production by the immunosuppressive agent, 15-deoxyspergualin. Transplant Proc 23:328–331Google Scholar
  196. 196.
    Ramya TN, Surolia N, Surolia A (2007) 15-deoxyspergualin inhibits eukaryotic protein synthesis through eIF2alpha phosphorylation. Biochem J 401:411–420CrossRefGoogle Scholar
  197. 197.
    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 64:99–107CrossRefGoogle Scholar
  198. 198.
    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 7:5–10CrossRefGoogle Scholar
  199. 199.
    Kaufman DB, Gores PF, Kelley S et al (1996) 15-deoxyspergualin: immunotherapy in solid organ and cellular transplantation. Transplant Rev 10:160–174CrossRefGoogle Scholar
  200. 200.
    Dhingra K, Valero V, Gutierrez L et al (1994) Phase II study of deoxyspergualin in metastatic breast cancer. Invest New Drugs 12:235–241CrossRefGoogle Scholar
  201. 201.
    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 42:277–290CrossRefGoogle Scholar
  202. 202.
    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 42:4749–4763CrossRefGoogle Scholar
  203. 203.
    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) 38:886–898CrossRefGoogle Scholar
  204. 204.
    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) 40:1303–1315CrossRefGoogle Scholar
  205. 205.
    Fewell SW, Day BW, Brodsky JL (2001) Identification of an inhibitor of hsc70-mediated protein translocation and ATP hydrolysis. J Biol Chem 276:910–914CrossRefGoogle Scholar
  206. 206.
    Fewell SW, Smith CM, Lyon MA et al (2004) Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. J Biol Chem 279:51131–51140CrossRefGoogle Scholar
  207. 207.
    Werner S, Turner DM, Lyon MA et al (2006) A focused library of tetrahydropyrimidinone amides via a tandem Biginelli-Ugi multi-component process. Synlett 2006:2334–2338CrossRefGoogle Scholar
  208. 208.
    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 Google Scholar
  209. 209.
    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 141:71–80CrossRefGoogle Scholar
  210. 210.
    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 16:3291–3301CrossRefGoogle Scholar
  211. 211.
    Jinwal UK, Miyata Y, Koren J 3rd et al (2009) Chemical manipulation of hsp70 ATPase activity regulates tau stability. J Neurosci 29:12079–12088CrossRefGoogle Scholar
  212. 212.
    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 5:611–622CrossRefGoogle Scholar
  213. 213.
    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 3:498–507CrossRefGoogle Scholar
  214. 214.
    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 ppGoogle Scholar
  215. 215.
    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 22:6490–6502CrossRefGoogle Scholar
  216. 216.
    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 283:27504–27513CrossRefGoogle Scholar
  217. 217.
    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 16:389–401CrossRefGoogle Scholar
  218. 218.
    Chiang AN, Valderramos J-C, Balachandran R et al (2009) Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorg Med Chem 17:1527–1533CrossRefGoogle Scholar
  219. 219.
    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 46:3–26CrossRefGoogle Scholar
  220. 220.
    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 108:6757–6762CrossRefGoogle Scholar
  221. 221.
    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 60:6818–6821Google Scholar
  222. 222.
    Tikoo A, Shakri R, Connolly L et al (2000) Treatment of ras-induced cancers by the F-actin-bundling drug MKT-077. Cancer J 6:162–168Google Scholar
  223. 223.
    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 56:538–543Google Scholar
  224. 224.
    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 10:923–927CrossRefGoogle Scholar
  225. 225.
    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 411:614–632CrossRefGoogle Scholar
  226. 226.
    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 4:1042–1047CrossRefGoogle Scholar
  227. 227.
    Whetstone H, Lingwood C (2003) 3′Sulfogalactolipid binding specifically inhibits Hsp70 ATPase activity in vitro. Biochemistry 42:1611–1617CrossRefGoogle Scholar
  228. 228.
    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 165:7–17CrossRefGoogle Scholar
  229. 229.
    Mamelak D, Lingood C (1997) Expression and sulfogalactolipid binding specificity of the recombinant testis-specific cognate heat shock protein 70. Glycoconj J 14:715–722CrossRefGoogle Scholar
  230. 230.
    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 40:3572–3582CrossRefGoogle Scholar
  231. 231.
    Mamelak D, Lingwood C (2001) The ATPase domain of hsp70 possesses a unique binding specificity for 3′-sulfogalactolipids. J Biol Chem 276:449–456CrossRefGoogle Scholar
  232. 232.
    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 335:91–100CrossRefGoogle Scholar
  233. 233.
    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 16:461–470CrossRefGoogle Scholar
  234. 234.
    De Rosa M, Park HJ, Mylvaganum M et al (2008) The medium is the message: glycosphingolipids and their soluble analogues. BBA Gen Sub 1780:347–352CrossRefGoogle Scholar
  235. 235.
    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 63:8233–8240Google Scholar
  236. 236.
    Gurbuxani S, Schmitt E, Cande C et al (2003) Heat shock protein 70 binding inhibits the nuclear import of apoptosis-inducing factor. Oncogene 22:6669–6678CrossRefGoogle Scholar
  237. 237.
    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 66:4191–4197CrossRefGoogle Scholar
  238. 238.
    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 120:457–471Google Scholar
  239. 239.
    Rérole A-L, Gobbo J, De Thonel A et al (2011) Peptides and aptamers targeting HSP70: a novel approach for anticancer chemotherapy. Cancer Res 71:484–495CrossRefGoogle Scholar
  240. 240.
    Jego G, Hazoumé A, Seigneuric R et al (2013) Targeting heat shock proteins in cancer. Cancer Lett 332:275–285CrossRefGoogle Scholar
  241. 241.
    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 47:7466–7469CrossRefGoogle Scholar
  242. 242.
    Shin I-j, Lee M-r, Williams D (2010) Imidazole derivatives that induce apoptosis and their therapeutic uses. United States PatentGoogle Scholar
  243. 243.
    Lev N, Melamed E, Offen D (2003) Apoptosis and Parkinson’s disease. Prog Neuropsychopharmacol 27:245–250CrossRefGoogle Scholar
  244. 244.
    Behl C (2000) Apoptosis and Alzheimer’s disease. J Neural Transm 107:1325–1344CrossRefGoogle Scholar
  245. 245.
    Meacham GC, Lu Z, King S et al (1999) The Hdj-2/Hsc70 chaperone pair facilitates early steps in CFTR biogenesis. EMBO J 18:1492–1505CrossRefGoogle Scholar
  246. 246.
    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 12:1303–1314CrossRefGoogle Scholar
  247. 247.
    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 52:1510–1513CrossRefGoogle Scholar
  248. 248.
    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 54:4034–4041CrossRefGoogle Scholar
  249. 249.
    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 68:498–505CrossRefGoogle Scholar
  250. 250.
    Li J, Lee AS (2006) Stress induction of GRP78/BiP and its role in cancer. Curr Mol Med 6:45–54CrossRefGoogle Scholar
  251. 251.
    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 66:535–545CrossRefGoogle Scholar
  252. 252.
    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 Google Scholar
  253. 253.
    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 22:551–563CrossRefGoogle Scholar
  254. 254.
    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 2:474–479CrossRefGoogle Scholar
  255. 255.
    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 21:3095–3109CrossRefGoogle Scholar
  256. 256.
    Leu JIJ, Pimkina J, Frank A et al (2009) A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 36:15–27CrossRefGoogle Scholar
  257. 257.
    Liu EY, Ryan KM (2012) Autophagy and cancer–issues we need to digest. J Cell Sci 125:2349–2358CrossRefGoogle Scholar
  258. 258.
    Balaburski GM, Leu JI, Beeharry N et al (2013) A modified HSP70 inhibitor shows broad activity as an anticancer agent. Mol Cancer Res 11:219–229CrossRefGoogle Scholar
  259. 259.
    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 9:936–947CrossRefGoogle Scholar
  260. 260.
    Kaiser M, Kuhnl A, Reins J et al (2011) Antileukemic activity of the HSP70 inhibitor pifithrin-mu in acute leukemia. Blood Cancer J 1:e28CrossRefGoogle Scholar
  261. 261.
    Pimkina JS, Murphy ME (2011) Interaction of the ARF tumor suppressor with cytosolic HSP70 contributes to its autophagy function. Cancer Biol Ther 12:503–509CrossRefGoogle Scholar
  262. 262.
    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 15:194–199CrossRefGoogle Scholar
  263. 263.
    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 2:43–46Google Scholar
  264. 264.
    Koren J, Jinwal UK, Jin Y et al (2010) Facilitating Akt clearance via manipulation of Hsp70 activity and levels. J Biol Chem 285:2498–2505CrossRefGoogle Scholar
  265. 265.
    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 18:210–221CrossRefGoogle Scholar
  266. 266.
    Medina DX, Caccamo A, Oddo S (2011) Methylene blue reduces Aβ levels and rescues early cognitive deficit by increasing proteasome activity. Brain Pathol 21:140–149CrossRefGoogle Scholar
  267. 267.
    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 20:1469–1480CrossRefGoogle Scholar
  268. 268.
    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 57:1188–1207CrossRefGoogle Scholar
  269. 269.
    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 57:1208–1224CrossRefGoogle Scholar
  270. 270.
    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 21:1648–1659CrossRefGoogle Scholar
  271. 271.
    Hassan AQ, Kirby Christina A, Zhou W et al (2015) The novolactone natural product disrupts the allosteric regulation of Hsp70. Chem Biol 22:87–97CrossRefGoogle Scholar
  272. 272.
    Ciocca DR, Arrigo AP, Calderwood SK (2013) Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update. Arch Toxicol 87:19–48CrossRefGoogle Scholar
  273. 273.
    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 160:465–476CrossRefGoogle Scholar
  274. 274.
    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 10:402–405CrossRefGoogle Scholar
  275. 275.
    Lanka V, Wieland S, Barber J et al (2009) Arimoclomol: a potential therapy under development for ALS. Expert Opin Invest Drugs 18:1907–1918CrossRefGoogle Scholar
  276. 276.
    Hosokawa N, Hirayoshi K, Nakai A et al (1990) Flavonoids inhibit the expression of heat shock proteins. Cell Struct Funct 15:393–401CrossRefGoogle Scholar
  277. 277.
    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 83:1216–1222CrossRefGoogle Scholar
  278. 278.
    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 12:3490–3498CrossRefGoogle Scholar
  279. 279.
    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 56:210–217Google Scholar
  280. 280.
    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 239:851–856CrossRefGoogle Scholar
  281. 281.
    Suolinna EM, Buchsbaum RN, Racker E (1975) The effect of flavonoids on aerobic glycolysis and growth of tumor cells. Cancer Res 35:1865–1872Google Scholar
  282. 282.
    Graziani Y, Chayoth R, Karny N et al (1982) Regulation of protein kinases activity by quercetin in Ehrlich ascites tumor cells. Biochim Biophys Acta 714:415–421CrossRefGoogle Scholar
  283. 283.
    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 38:291–304CrossRefGoogle Scholar
  284. 284.
    Ma Y, Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe? Nat Rev Cancer 4:966–977CrossRefGoogle Scholar
  285. 285.
    Boulton DW, Walle UK, Walle T (1999) Fate of the flavonoid quercetin in human cell lines: chemical instability and metabolism. J Pharm Pharmacol 51:353–359CrossRefGoogle Scholar
  286. 286.
    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 148:521–530CrossRefGoogle Scholar
  287. 287.
    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 60:2942–2948Google Scholar
  288. 288.
    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 7:215–219Google Scholar
  289. 289.
    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 80:607–614CrossRefGoogle Scholar
  290. 290.
    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 4:1–18CrossRefGoogle Scholar
  291. 291.
    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 281:9616–9622CrossRefGoogle Scholar
  292. 292.
    Phillips PA, Dudeja V, McCarroll JA et al (2007) Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res 67:9407–9416CrossRefGoogle Scholar
  293. 293.
    Antonoff MB, Chugh R, Skube SJ et al (2010) Role of Hsp-70 in triptolide-mediated cell death of neuroblastoma. J Surg Res 163:72–78CrossRefGoogle Scholar
  294. 294.
    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 217:28–37CrossRefGoogle Scholar
  295. 295.
    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 318:145–153CrossRefGoogle Scholar
  296. 296.
    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 52:6083–6096CrossRefGoogle Scholar
  297. 297.
    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 150:549–562CrossRefGoogle Scholar
  298. 298.
    van der Putten H, Lotz G (2013) Opportunities and challenges for molecular chaperone modulation to treat protein-conformational brain diseases. Neurotherapeutics 10:416–428CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Alexandra Manos-Turvey
    • 1
    • 2
  • Jeffrey L. Brodsky
    • 1
  • Peter Wipf
    • 2
  1. 1.Department of Biological SciencesUniversity of PittsburghPittsburghUSA
  2. 2.Department of ChemistryUniversity of PittsburghPittsburghUSA

Personalised recommendations