Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Part of the Topics in Medicinal Chemistry book series (TMC, volume 19)


Cancer cells survive in the presence of stresses that would normally cause cell death. To accomplish this feat, they express elevated levels of the molecular chaperones: heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). Knockdown of these chaperones is selectively toxic to cancer cells, suggesting that they might be promising nodes for anticancer therapy. However, while inhibitors of Hsp90 are well known, progress in the development of Hsp70 inhibitors has proven more difficult. Hsp70 binds tightly to ATP through a highly conserved domain of the actin/hexokinase superfamily, making it challenging to identify selective, competitive inhibitors. Despite this obstacle, progress has been made and first-generation molecules are being deployed. To supplement these efforts, compounds that target important allosteric sites on the chaperone have also been discovered. In some of these cases, the molecules have been shown to control key protein–protein interactions between Hsp70 and its co-chaperones. In other cases, allosteric sites have been used to gain unexpected selectivity for members of the Hsp70 family. Here, we review recent progress in the development of Hsp70 inhibitors.


Allosteric inhibitors Chaperones Dihydropyrimidines MKT-077 Protein folding Protein–protein interactions Spergualin 



Our work on Hsp70 is funded by the NIH (NS059690). We thank the members of our group for useful feedback and advice.


  1. 1.
    Powers MV, Workman P (2007) Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581:3758–3769CrossRefGoogle Scholar
  2. 2.
    Trepel J, Mollapour M, Giaccone G et al (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10:537–549CrossRefGoogle Scholar
  3. 3.
    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
  4. 4.
    Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823–837CrossRefGoogle Scholar
  5. 5.
    Ferrarini M, Heltai S, Zocchi MR et al (1992) Unusual expression and localization of heat-shock proteins in human tumor cells. Int J Cancer 51:613–619CrossRefGoogle Scholar
  6. 6.
    Gress TM, Muller-Pillasch F, Weber C et al (1994) Differential expression of heat shock proteins in pancreatic carcinoma. Cancer Res 54:547–551Google Scholar
  7. 7.
    Yaglom JA, Gabai VL, Sherman MY (2007) High levels of heat shock protein Hsp72 in cancer cells suppress default senescence pathways. Cancer Res 67:2373–2381CrossRefGoogle Scholar
  8. 8.
    Abdel-Magid AF, Carson KG, Harris BD et al (1996) Reductive amination of aldehydes and ketones with sodium triacetoxyborohydride. Studies on direct and indirect reductive amination procedures(1). J Org Chem 61:3849–3862CrossRefGoogle Scholar
  9. 9.
    Gabai VL, Budagova KR, Sherman MY (2005) Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents. Oncogene 24:3328–3338CrossRefGoogle Scholar
  10. 10.
    Gabai VL, Yaglom JA, Waldman T et al (2009) Heat shock protein Hsp72 controls oncogene-induced senescence pathways in cancer cells. Mol Cell Biol 29:559–569CrossRefGoogle Scholar
  11. 11.
    Yano M, Naito Z, Tanaka S et al (1996) Expression and roles of heat shock proteins in human breast cancer. Jpn J Cancer Res 87:908–915CrossRefGoogle Scholar
  12. 12.
    Li J, Buchner J (2013) Structure, function and regulation of the hsp90 machinery. Biomed J 36:106–117CrossRefGoogle Scholar
  13. 13.
    Miyata Y, Nakamoto H, Neckers L (2013) The therapeutic target Hsp90 and cancer hallmarks. Curr Pharm Des 19:347–365CrossRefGoogle Scholar
  14. 14.
    Pearl LH, Prodromou C (2006) Structure and mechanism of the Hsp90 molecular chaperone machinery. Annu Rev Biochem 75:271–294CrossRefGoogle Scholar
  15. 15.
    Krukenberg KA, Street TO, Lavery LA et al (2011) Conformational dynamics of the molecular chaperone Hsp90. Q Rev Biophys 44:229–255CrossRefGoogle Scholar
  16. 16.
    Southworth DR, Agard DA (2008) Species-dependent ensembles of conserved conformational states define the Hsp90 chaperone ATPase cycle. Mol Cell 32:631–640CrossRefGoogle Scholar
  17. 17.
    Lavery LA, Partridge JR, Ramelot TA et al (2014) Structural asymmetry in the closed state of mitochondrial Hsp90 (TRAP1) supports a two-step ATP hydrolysis mechanism. Mol Cell 53:330–343CrossRefGoogle Scholar
  18. 18.
    Kirschke E, Goswami D, Southworth D et al (2014) Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles. Cell 157:1685–1697CrossRefGoogle Scholar
  19. 19.
    Powers MV, Clarke PA, Workman P (2009) Death by chaperone: HSP90, HSP70 or both? Cell Cycle 8:518–526CrossRefGoogle Scholar
  20. 20.
    Samant RS, Clarke PA, Workman P (2012) The expanding proteome of the molecular chaperone HSP90. Cell Cycle 11:1301–1308CrossRefGoogle Scholar
  21. 21.
    Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat Rev Mol Cell Biol 11:515–528CrossRefGoogle Scholar
  22. 22.
    Taipale M, Krykbaeva I, Koeva M et al (2012) Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 150:987–1001CrossRefGoogle Scholar
  23. 23.
    Pratt WB, Morishima Y, Gestwicki JE et al (2014) A model in which heat shock protein 90 targets protein-folding clefts: rationale for a new approach to neuroprotective treatment of protein folding diseases. Exp Biol Med (Maywood) 239:1405–1413CrossRefGoogle Scholar
  24. 24.
    Connell P, Ballinger CA, Jiang J et al (2001) The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol 3:93–96CrossRefGoogle Scholar
  25. 25.
    Xu W, Mimnaugh EG, Kim JS et al (2002) Hsp90, not Grp94, regulates the intracellular trafficking and stability of nascent ErbB2. Cell Stress Chaperones 7:91–96CrossRefGoogle Scholar
  26. 26.
    Pearl LH, Prodromou C, Workman P (2008) The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem J 410:439–453CrossRefGoogle Scholar
  27. 27.
    Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772CrossRefGoogle Scholar
  28. 28.
    Chaudhury S, Welch TR, Blagg BS (2006) Hsp90 as a target for drug development. ChemMedChem 1:1331–1340Google Scholar
  29. 29.
    Schulte TW, Akinaga S, Soga S et al (1998) Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin. Cell Stress Chaperones 3:100–108CrossRefGoogle Scholar
  30. 30.
    Schulte TW, Neckers LM (1998) The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin. Cancer Chemother Pharmacol 42:273–279CrossRefGoogle Scholar
  31. 31.
    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
  32. 32.
    Donnelly A, Blagg BS (2008) Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr Med Chem 15:2702–2717CrossRefGoogle Scholar
  33. 33.
    Eskew JD, Sadikot T, Morales P et al (2011) Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells. BMC Cancer 11:468CrossRefGoogle Scholar
  34. 34.
    Patwardhan CA, Fauq A, Peterson LB et al (2013) Gedunin inactivates the co-chaperone p23 protein causing cancer cell death by apoptosis. J Biol Chem 288:7313–7325CrossRefGoogle Scholar
  35. 35.
    Pimienta G, Herbert KM, Regan L (2011) A compound that inhibits the HOP-Hsp90 complex formation and has unique killing effects in breast cancer cell lines. Mol Pharm 8:2252–2261CrossRefGoogle Scholar
  36. 36.
    Zhang T, Hamza A, Cao X et al (2008) A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol Cancer Ther 7:162–170CrossRefGoogle Scholar
  37. 37.
    Ardi VC, Alexander LD, Johnson VA et al (2011) Macrocycles that inhibit the binding between heat shock protein 90 and TPR-containing proteins. ACS Chem Biol 6:1357–1366CrossRefGoogle Scholar
  38. 38.
    Zuehlke A, Johnson JL (2010) Hsp90 and co-chaperones twist the functions of diverse client proteins. Biopolymers 93:211–217CrossRefGoogle Scholar
  39. 39.
    Li J, Soroka J, Buchner J (2012) The Hsp90 chaperone machinery: conformational dynamics and regulation by co-chaperones. Biochim Biophys Acta 1823:624–635CrossRefGoogle Scholar
  40. 40.
    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
  41. 41.
    Rohl A, Rohrberg J, Buchner J (2013) The chaperone Hsp90: changing partners for demanding clients. Trends Biochem Sci 38:253–262CrossRefGoogle Scholar
  42. 42.
    Vasko RC, Rodriguez RA, Cunningham CN et al (2010) Mechanistic studies of Sansalvamide A-amide: an allosteric modulator of Hsp90. ACS Med Chem Lett 1:4–8CrossRefGoogle Scholar
  43. 43.
    McConnell JR, Alexander LA, McAlpine SR (2014) A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response. Bioorg Med Chem Lett 24:661–666CrossRefGoogle Scholar
  44. 44.
    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
  45. 45.
    Bork P, Sander C, Valencia A (1992) An ATPase domain common to prokaryotic cell cycle proteins, sugar kinases, actin, and hsp70 heat shock proteins. Proc Natl Acad Sci U S A 89:7290–7294CrossRefGoogle Scholar
  46. 46.
    Massey AJ (2010) ATPases as drug targets: insights from heat shock proteins 70 and 90. J Med Chem 53:7280–7286CrossRefGoogle Scholar
  47. 47.
    Wang H, Kurochkin AV, Pang Y et al (1998) NMR solution structure of the 21 kDa chaperone protein DnaK substrate binding domain: a preview of chaperone-protein interaction. Biochemistry 37:7929–7940CrossRefGoogle Scholar
  48. 48.
    Smock RG, Rivoire O, Russ WP et al (2010) An interdomain sector mediating allostery in Hsp70 molecular chaperones. Mol Syst Biol 6:414CrossRefGoogle Scholar
  49. 49.
    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
  50. 50.
    Zuiderweg ER, Bertelsen EB, Rousaki A et al (2013) Allostery in the Hsp70 chaperone proteins. Top Curr Chem 328:99–153CrossRefGoogle Scholar
  51. 51.
    Zhang Y, Zuiderweg ER (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
  52. 52.
    Ahmad A, Bhattacharya A, McDonald RA et al (2011) Heat shock protein 70 kDa chaperone/DnaJ cochaperone complex employs an unusual dynamic interface. Proc Natl Acad Sci U S A 108:18966–18971CrossRefGoogle Scholar
  53. 53.
    Mayer MP, Schroder H, Rudiger S et al (2000) Multistep mechanism of substrate binding determines chaperone activity of Hsp70. Nat Struct Biol 7:586–593CrossRefGoogle Scholar
  54. 54.
    Vogel M, Bukau B, Mayer MP (2006) Allosteric regulation of Hsp70 chaperones by a proline switch. Mol Cell 21:359–367CrossRefGoogle Scholar
  55. 55.
    General IJ, Liu Y, Blackburn ME et al (2014) ATPase subdomain IA is a mediator of interdomain allostery in Hsp70 molecular chaperones. PLoS Comput Biol 10, e1003624CrossRefGoogle Scholar
  56. 56.
    Assimon VA, Gillies AT, Rauch JN et al (2013) Hsp70 protein complexes as drug targets. Curr Pharm Des 19:404–417CrossRefGoogle Scholar
  57. 57.
    Rauch JN, Gestwicki JE (2014) Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro. J Biol Chem 289:1402–1414CrossRefGoogle Scholar
  58. 58.
    Sondermann H, Scheufler C, Schneider C et al (2001) Structure of a Bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors. Science 291:1553–1557CrossRefGoogle Scholar
  59. 59.
    Liu FH, Wu SJ, Hu SM et al (1999) Specific interaction of the 70-kDa heat shock cognate protein with the tetratricopeptide repeats. J Biol Chem 274:34425–34432CrossRefGoogle Scholar
  60. 60.
    Connarn JN, Assimon VA, Reed RA et al (2014) The molecular chaperone Hsp70 activates protein phosphatase 5 (PP5) by binding the tetratricopeptide repeat (TPR) domain. J Biol Chem 289:2908–2917CrossRefGoogle Scholar
  61. 61.
    Smith MC, Scaglione KM, Assimon VA et al (2013) The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex. Biochemistry 52:5354–5364CrossRefGoogle Scholar
  62. 62.
    Cortajarena AL, Regan L (2006) Ligand binding by TPR domains. Protein Sci 15:1193–1198CrossRefGoogle Scholar
  63. 63.
    Chen S, Smith DF (1998) Hop as an adaptor in the heat shock protein 70 (Hsp70) and hsp90 chaperone machinery. J Biol Chem 273:35194–35200CrossRefGoogle Scholar
  64. 64.
    Johnson BD, Schumacher RJ, Ross ED et al (1998) Hop modulates Hsp70/Hsp90 interactions in protein folding. J Biol Chem 273:3679–3686CrossRefGoogle Scholar
  65. 65.
    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
  66. 66.
    Hohfeld J, Cyr DM, Patterson C (2001) From the cradle to the grave: molecular chaperones that may choose between folding and degradation. EMBO Rep 2:885–890CrossRefGoogle Scholar
  67. 67.
    Muller P, Ruckova E, Halada P et al (2012) C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances. Oncogene. doi: 10.1038/onc.2012.314 Google Scholar
  68. 68.
    Rudiger S, Germeroth L, Schneider-Mergener J et al (1997) Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries. EMBO J 16:1501–1507CrossRefGoogle Scholar
  69. 69.
    Zhu X, Zhao X, Burkholder WF et al (1996) Structural analysis of substrate binding by the molecular chaperone DnaK. Science 272:1606–1614CrossRefGoogle Scholar
  70. 70.
    Srinivasan SR, Gillies AT, Chang L et al (2012) Molecular chaperones DnaK and DnaJ share predicted binding sites on most proteins in the E. coli proteome. Mol BioSyst 8:2323–2333CrossRefGoogle Scholar
  71. 71.
    Koren J 3rd, Jinwal UK, Jin Y et al (2010) Facilitating Akt clearance via manipulation of Hsp70 activity and levels. J Biol Chem 285:2498–2505CrossRefGoogle Scholar
  72. 72.
    Meng L, Hunt C, Yaglom JA et al (2011) Heat shock protein Hsp72 plays an essential role in Her2-induced mammary tumorigenesis. Oncogene 30:2836–2845CrossRefGoogle Scholar
  73. 73.
    Powers MV, Clarke PA, Workman P (2008) Dual targeting of HSC70 and HSP72 inhibits HSP90 function and induces tumor-specific apoptosis. Cancer Cell 14:250–262CrossRefGoogle Scholar
  74. 74.
    Powers MV, Jones K, Barillari C et al (2010) Targeting HSP70: the second potentially druggable heat shock protein and molecular chaperone? Cell Cycle 9:1542–1550CrossRefGoogle Scholar
  75. 75.
    Walerych D, Olszewski MB, Gutkowska M et al (2009) Hsp70 molecular chaperones are required to support p53 tumor suppressor activity under stress conditions. Oncogene 28:4284–4294CrossRefGoogle Scholar
  76. 76.
    Barouch W, Prasad K, Greene LE et al (1994) ATPase activity associated with the uncoating of clathrin baskets by Hsp70. J Biol Chem 269:28563–28568Google Scholar
  77. 77.
    Jaattela M (1999) Heat shock proteins as cellular lifeguards. Ann Med 31:261–271CrossRefGoogle Scholar
  78. 78.
    Sherman MY, Gabai VL (2014) Hsp70 in cancer: back to the future. Oncogene. doi: 10.1038/onc.2014.349 Google Scholar
  79. 79.
    Jaattela M (1995) Over-expression of hsp70 confers tumorigenicity to mouse fibrosarcoma cells. Int J Cancer 60:689–693CrossRefGoogle Scholar
  80. 80.
    Ran Q, Wadhwa R, Kawai R et al (2000) Extramitochondrial localization of mortalin/mthsp70/PBP74/GRP75. Biochem Biophys Res Commun 275:174–179CrossRefGoogle Scholar
  81. 81.
    Lu WJ, Lee NP, Kaul SC et al (2011) Mortalin-p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy. Cell Death Differ 18:1046–1056CrossRefGoogle Scholar
  82. 82.
    Knittler MR, Dirks S, Haas IG (1995) Molecular chaperones involved in protein degradation in the endoplasmic reticulum: quantitative interaction of the heat shock cognate protein BiP with partially folded immunoglobulin light chains that are degraded in the endoplasmic reticulum. Proc Natl Acad Sci U S A 92:1764–1768CrossRefGoogle Scholar
  83. 83.
    Deocaris CC, Widodo N, Shrestha BG et al (2007) Mortalin sensitizes human cancer cells to MKT-077-induced senescence. Cancer Lett 252:259–269CrossRefGoogle Scholar
  84. 84.
    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
  85. 85.
    Nylandsted J, Brand K, Jaattela M (2000) Heat shock protein 70 is required for the survival of cancer cells. Ann N Y Acad Sci 926:122–125CrossRefGoogle Scholar
  86. 86.
    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
  87. 87.
    Nanbu K, Konishi I, Mandai M et al (1998) Prognostic significance of heat shock proteins HSP70 and HSP90 in endometrial carcinomas. Cancer Detect Prev 22:549–555CrossRefGoogle Scholar
  88. 88.
    Ciocca DR, Calderwood SK (2005) Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:86–103CrossRefGoogle Scholar
  89. 89.
    Jaattela M (1993) Overexpression of major heat shock protein hsp70 inhibits tumor necrosis factor-induced activation of phospholipase A2. J Immunol 151:4286–4294Google Scholar
  90. 90.
    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
  91. 91.
    Park HS, Lee JS, Huh SH et al (2001) Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J 20:446–456CrossRefGoogle Scholar
  92. 92.
    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
  93. 93.
    Ravagnan L, Gurbuxani S, Susin SA et al (2001) Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nat Cell Biol 3:839–843CrossRefGoogle Scholar
  94. 94.
    Guo F, Sigua C, Bali P et al (2005) Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood 105:1246–1255CrossRefGoogle Scholar
  95. 95.
    Gotoh T, Terada K, Oyadomari S et al (2004) hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria. Cell Death Differ 11:390–402CrossRefGoogle Scholar
  96. 96.
    Stankiewicz AR, Lachapelle G, Foo CP et al (2005) Hsp70 inhibits heat-induced apoptosis upstream of mitochondria by preventing Bax translocation. J Biol Chem 280:38729–38739CrossRefGoogle Scholar
  97. 97.
    Colvin TA, Gabai VL, Gong J et al (2014) Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer Res 74:4731–4740CrossRefGoogle Scholar
  98. 98.
    Kabakov AE, Gabai VL (1995) Heat shock-induced accumulation of 70-kDa stress protein (HSP70) can protect ATP-depleted tumor cells from necrosis. Exp Cell Res 217:15–21CrossRefGoogle Scholar
  99. 99.
    Leu JI, Pimkina J, Frank A et al (2009) A small molecule inhibitor of inducible heat shock protein 70. Mol Cell 36:15–27CrossRefGoogle Scholar
  100. 100.
    Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem 53:4585–4602CrossRefGoogle Scholar
  101. 101.
    Patury S, Miyata Y, Gestwicki JE (2009) Pharmacological targeting of the Hsp70 chaperone. Curr Top Med Chem 9:1337–1351CrossRefGoogle Scholar
  102. 102.
    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
  103. 103.
    Repalli J, Meruelo D (2015) Screening strategies to identify HSP70 modulators to treat Alzheimer's disease. Drug Des Devel Ther 9:321–331CrossRefGoogle Scholar
  104. 104.
    Leu JI, Zhang P, Murphy ME et al (2014) Structural basis for the inhibition of HSP70 and DnaK chaperones by small-molecule targeting of a C-terminal allosteric pocket. ACS Chem Biol 9:2508–2516CrossRefGoogle Scholar
  105. 105.
    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
  106. 106.
    Leu JI, 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
  107. 107.
    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
  108. 108.
    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
  109. 109.
    Davis MJ, Gregorka B, Gestwicki JE et al (2012) Inducible renitence limits Listeria monocytogenes escape from vacuoles in macrophages. J Immunol 189:4488–4495CrossRefGoogle Scholar
  110. 110.
    Schmitt E, Maingret L, Puig PE 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
  111. 111.
    Umezawa H, Kondo S, Iinuma H et al (1981) Structure of an antitumor antibiotic, spergualin. J Antibiot (Tokyo) 34:1622–1624CrossRefGoogle Scholar
  112. 112.
    Nishikawa K, Shibasaki C, Takahashi K et al (1986) Antitumor activity of spergualin, a novel antitumor antibiotic. J Antibiot (Tokyo) 39:1461–1466CrossRefGoogle Scholar
  113. 113.
    Nemoto K, Abe F, Takita T et al (1987) Suppression of experimental allergic encephalomyelitis in guinea pigs by spergualin and 15-deoxyspergualin. J Antibiot (Tokyo) 40:1193–1194CrossRefGoogle Scholar
  114. 114.
    Nemoto K, Hayashi M, Abe F et al (1987) Suppression of humoral immunity in mice by spergualin. Transplant Proc 19:4638–4640Google Scholar
  115. 115.
    Nishizawa R, Takei Y, Yoshida M et al (1988) Synthesis and biological activity of spergualin analogues. I J Antibiot (Tokyo) 41:1629–1643CrossRefGoogle Scholar
  116. 116.
    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
  117. 117.
    Krieger NR, Emre S (2004) Novel immunosuppressants. Pediatr Transplant 8:594–599CrossRefGoogle Scholar
  118. 118.
    Kaufman DB, Gores PF, Kelley S et al (1996) 15-Deoxyspergualin: Immunotherapy in solid organ and cellular transplantation. Transplant Rev 10:160–174CrossRefGoogle Scholar
  119. 119.
    Elices MJ (2001) Tresperimus (Laboratoires Fournier). Curr Opin Investig Drugs 2:372–374Google Scholar
  120. 120.
    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
  121. 121.
    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
  122. 122.
    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
  123. 123.
    Havlin KA, Kuhn JG, Koeller J et al (1995) Deoxyspergualin: phase I clinical, immunologic and pharmacokinetic study. Anticancer Drugs 6:229–236CrossRefGoogle Scholar
  124. 124.
    Hassan AQ, Kirby CA, Zhou W et al (2015) The novolactone natural product disrupts the allosteric regulation of hsp70. Chem Biol 22:87–97CrossRefGoogle Scholar
  125. 125.
    Kragol G, Lovas S, Varadi G et al (2001) The antibacterial peptide pyrrhocoricin inhibits the ATPase actions of DnaK and prevents chaperone-assisted protein folding. Biochemistry 40:3016–3026CrossRefGoogle Scholar
  126. 126.
    Cellitti J, Zhang Z, Wang S et al (2009) Small molecule DnaK modulators targeting the beta-domain. Chem Biol Drug Des 74:349–357CrossRefGoogle Scholar
  127. 127.
    Williams DR, Ko SK, Park S et al (2008) An apoptosis-inducing small molecule that binds to heat shock protein 70. Angew Chem Int Ed Engl 47:7466–7469CrossRefGoogle Scholar
  128. 128.
    Cho HJ, Gee HY, Baek KH et al (2011) A small molecule that binds to an ATPase domain of Hsc70 promotes membrane trafficking of mutant cystic fibrosis transmembrane conductance regulator. Journal of the American Chemical Society 133:20267–20276CrossRefGoogle Scholar
  129. 129.
    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
  130. 130.
    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
  131. 131.
    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
  132. 132.
    Wisen 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 chemical biology 5:611–622CrossRefGoogle Scholar
  133. 133.
    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
  134. 134.
    Wisen S, Androsavich J, Evans CG et al (2008) Chemical modulators of heat shock protein 70 (Hsp70) by sequential, microwave-accelerated reactions on solid phase. Bioorg Med Chem Lett 18:60–65CrossRefGoogle Scholar
  135. 135.
    Chang L, Bertelsen EB, Wisén S et al (2008) High-throughput screen for small molecules that modulate the ATPase activity of the molecular chaperone DnaK. Anal Biochem 372:167–176CrossRefGoogle Scholar
  136. 136.
    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
  137. 137.
    Wisen S, Gestwicki JE (2008) Identification of small molecules that modify the protein folding activity of heat shock protein 70. Anal Biochem 374:371–377CrossRefGoogle Scholar
  138. 138.
    Braunstein MJ, Scott SS, Scott CM et al (2011) Antimyeloma Effects of the Heat Shock Protein 70 Molecular Chaperone Inhibitor MAL3-101. J Oncol 2011:232037CrossRefGoogle Scholar
  139. 139.
    Adam C, Baeurle A, Brodsky JL et al (2014) The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma. PLoS One 9, e92041CrossRefGoogle Scholar
  140. 140.
    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
  141. 141.
    Chiba Y, Kubota T, Watanabe M et al (1998) MKT-077, localized lipophilic cation: antitumor activity against human tumor xenografts serially transplanted into nude mice. Anticancer Res 18:1047–1052Google Scholar
  142. 142.
    Chiba Y, Kubota T, Watanabe M et al (1998) Selective antitumor activity of MKT-077, a delocalized lipophilic cation, on normal cells and cancer cells in vitro. J Surg Oncol 69:105–110CrossRefGoogle Scholar
  143. 143.
    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
  144. 144.
    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
  145. 145.
    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
  146. 146.
    Wang AM, Miyata Y, Klinedinst S et al (2013) Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat Chem Biol 9:112–118CrossRefGoogle Scholar
  147. 147.
    Miyata Y, Li X, Lee HF et al (2013) Synthesis and initial evaluation of YM-08, a blood-brain barrier permeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT-077. Which reduces Tau levels. ACS Chem Neurosci. doi: 10.1021/cn300210g Google Scholar
  148. 148.
    Koren J 3rd, Miyata Y, Kiray J et al (2012) Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance. PLoS One 7, e35566CrossRefGoogle Scholar
  149. 149.
    Li X, Srinivasan SR, Connarn J et al (2013) Analogs of the allosteric heat shock protein 70 (Hsp70) inhibitor, MKT-077, as anti-cancer agents. ACS Med Chem Lett 2013:4Google Scholar
  150. 150.
    Miyata Y, Koren J, Kiray J et al (2011) Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies. Future Med Chem 3:1523–1537CrossRefGoogle Scholar
  151. 151.
    Kawakami M, Koya K, Ukai T et al (1998) Structure-activity of novel rhodacyanine dyes as antitumor agents. J Med Chem 41:130–142CrossRefGoogle Scholar
  152. 152.
    Takasu K, Terauchi H, Inoue H et al (2003) Parallel synthesis of antimalarial rhodacyanine dyes by the combination of three components in one pot. J Comb Chem 5:211–214CrossRefGoogle Scholar
  153. 153.
    Kasmi-Mir S, Djafri A, Hamelin J et al (2007) Synthesis of new rhodacyanines analogous to MKT-077 under microwave irradiation. Synt Commun 37:4017–4034CrossRefGoogle Scholar
  154. 154.
    Tatsuta N, Suzuki N, Mochizuki T et al (1999) Pharmacokinetic analysis and antitumor efficacy of MKT-077, a novel antitumor agent. Cancer Chemother Pharmacol 43:295–301CrossRefGoogle Scholar
  155. 155.
    Li X, Colvin T, Rauch JN et al (2015) Validation of the Hsp70-Bag3 protein–protein interaction as a potential therapeutic target in cancer. Mol Cancer Ther. doi: 10.1158/1535-7163.MCT-14-0650 Google Scholar
  156. 156.
    Rodina A, Patel PD, 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
  157. 157.
    Miyata Y, Rauch JN, Jinwal UK et al (2012) Cysteine reactivity distinguishes redox sensing by the heat-inducible and constitutive forms of heat shock protein 70. Chem Biol 19:1391–1399CrossRefGoogle Scholar
  158. 158.
    Wang Y, Gibney PA, West JD et al (2012) The yeast Hsp70 Ssa1 is a sensor for activation of the heat shock response by thiol-reactive compounds. Mol Biol Cell 23:3290–3298CrossRefGoogle Scholar
  159. 159.
    Rodina A, Taldone T, Kang Y et al (2014) Affinity purification probes of potential use to investigate the endogenous Hsp70 interactome in cancer. ACS Chem Biol 9:1698–1705CrossRefGoogle Scholar
  160. 160.
    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
  161. 161.
    Howe MK, Bodoor K, Carlson DA 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
  162. 162.
    Daguer JP, Zambaldo C, Ciobanu M et al (2015) DNA display of fragment pairs as a tool for the discovery of novel biologically active small molecules. Chem Rev 6:739–744Google Scholar
  163. 163.
    McNamara AV, Barclay M, Watson AJ et al (2012) Hsp90 inhibitors sensitise human colon cancer cells to topoisomerase I poisons by depletion of key anti-apoptotic and cell cycle checkpoint proteins. Biochem Pharmacol 83:355–367CrossRefGoogle Scholar
  164. 164.
    Stingl L, Stuhmer T, Chatterjee M et al (2010) Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction. Br J Cancer 102:1578–1591CrossRefGoogle Scholar
  165. 165.
    Wainberg ZA, Anghel A, Rogers AM et al (2013) Inhibition of HSP90 with AUY922 induces synergy in HER2-amplified trastuzumab-resistant breast and gastric cancer. Mol Cancer Ther 12:509–519CrossRefGoogle Scholar
  166. 166.
    Lu X, Xiao L, Wang L et al (2012) Hsp90 inhibitors and drug resistance in cancer: the potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs. Biochem Pharmacol 83:995–1004CrossRefGoogle Scholar
  167. 167.
    Tatokoro M, Koga F, Yoshida S et al (2012) Potential role of Hsp90 inhibitors in overcoming cisplatin resistance of bladder cancer-initiating cells. Int J Cancer 131:987–996CrossRefGoogle Scholar
  168. 168.
    Zhang H, Neely L, Lundgren K et al (2010) BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance. Int J Cancer 126:1226–1234CrossRefGoogle Scholar
  169. 169.
    Goloudina AR, Demidov ON, Garrido C (2012) Inhibition of HSP70: a challenging anti-cancer strategy. Cancer Lett 325:117–124CrossRefGoogle Scholar
  170. 170.
    Davenport EL, Zeisig A, Aronson LI et al (2010) Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma. Leukemia 24:1804–1807CrossRefGoogle Scholar
  171. 171.
    Wang Y, McAlpine SR (2015) Regulating the cytoprotective response in cancer cells using simultaneous inhibition of Hsp90 and Hsp70. Org Biomol Chem 13:2108–2116CrossRefGoogle Scholar
  172. 172.
    Wang Y, McAlpine SR (2015) N-terminal and C-terminal modulation of Hsp90 produce dissimilar phenotypes. Chem Commun (Camb) 51:1410–1413CrossRefGoogle Scholar
  173. 173.
    Crawford LJ, Walker B, Irvine AE (2011) Proteasome inhibitors in cancer therapy. J Cell Commun Signal 5:101–110CrossRefGoogle Scholar
  174. 174.
    Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7:961–967CrossRefGoogle Scholar
  175. 175.
    Gaspar N, Sharp SY, Pacey S et al (2009) Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells. Cancer Res 69:1966–1975CrossRefGoogle Scholar
  176. 176.
    Kummar S, Gutierrez ME, Gardner ER et al (2010) Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Eur J Cancer 46:340–347CrossRefGoogle Scholar
  177. 177.
    Lancet JE, Gojo I, Burton M et al (2010) Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia. Leukemia 24:699–705CrossRefGoogle Scholar
  178. 178.
    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 15:1–6CrossRefGoogle Scholar
  179. 179.
    Bercovich B, Stancovski I, Mayer A et al (1997) Ubiquitin-dependent degradation of certain protein substrates in vitro requires the molecular chaperone Hsc70. J Biol Chem 272:9002–9010CrossRefGoogle Scholar
  180. 180.
    Frydman J (2001) Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem 70:603–647CrossRefGoogle Scholar
  181. 181.
    Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332CrossRefGoogle Scholar
  182. 182.
    Kettern N, Rogon C, Limmer A et al (2011) The Hsc/Hsp70 co-chaperone network controls antigen aggregation and presentation during maturation of professional antigen presenting cells. PLoS One 6, e16398CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Chemical Biology Graduate ProgramUniversity of MichiganAnn ArborUSA
  2. 2.Department of Pharmaceutical ChemistryUniversity of California at San FranciscoSan FranciscoUSA

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