• 中国中文核心期刊
  • 中国科学引文数据库核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
高级检索

以热休克蛋白HSP70为靶点的药物研究进展

刘宗亮, 张仁梅, 孟庆国

刘宗亮, 张仁梅, 孟庆国. 以热休克蛋白HSP70为靶点的药物研究进展[J]. 中国药科大学学报, 2017, 48(4): 416-424. DOI: 10.11665/j.issn.1000-5048.20170405
引用本文: 刘宗亮, 张仁梅, 孟庆国. 以热休克蛋白HSP70为靶点的药物研究进展[J]. 中国药科大学学报, 2017, 48(4): 416-424. DOI: 10.11665/j.issn.1000-5048.20170405
LIU Zongliang, ZHANG Renmei, MENG Qingguo. Advances of targeting heat shock protein 70 drugs[J]. Journal of China Pharmaceutical University, 2017, 48(4): 416-424. DOI: 10.11665/j.issn.1000-5048.20170405
Citation: LIU Zongliang, ZHANG Renmei, MENG Qingguo. Advances of targeting heat shock protein 70 drugs[J]. Journal of China Pharmaceutical University, 2017, 48(4): 416-424. DOI: 10.11665/j.issn.1000-5048.20170405

以热休克蛋白HSP70为靶点的药物研究进展

基金项目: 国家自然科学基金资助项目(No.81502983)

Advances of targeting heat shock protein 70 drugs

  • 摘要: 热休克蛋白HSP70是最保守的蛋白之一,由于在应激反应中的敏感性以及功能的多样性,HSP70逐渐成为研究的热点。HSP70蛋白可以结合错误折叠或非正常聚集的蛋白,使之正常折叠或降解,因此合理干预HSP70的生物功能,可有望治疗一系列与蛋白错误折叠相关的疾病,如肿瘤和神经退行性疾病等。目前已有多类以HSP70为靶点的药物处于临床前研究中。本文综述了HSP70的分类、结构、功能及以HSP70为靶点的药物研究进展。
    Abstract: Heat shock protein 70(HSP70)family is one ofthe most conserved proteinin evolutionand plays critical, role in proteostasis. HSP70 is becoming an interesting target for multiple diseases such as cancer and Alzheimer′s disease. There are many drugs targeted to HSP70 in preclinical study. In this review, the classification, the structure, the function of HSP70, and the drugs of the HSP70 family are reviewed.
  • [1] Ritossa F.A new puffing pattern induced by temperature shock and DNP in Drosophila[J].Experientia,1962,18(12):571-573.
    [2] Lindquist S.The heat-shock response[J].Annu Rev Biochen,1986,55(1):1151-1191.
    [3] Turturici G,Sconzo G,Geraci F.Hsp70 and its molecular role in nervous system diseases[J].Biochem Res Int,2011,2011(4096):618127.
    [4] Schlesinger MJ.Heat shock proteins:the search for functions[J].J Cell Biol,1986,103(2):321-325.
    [5] Murphy ME.The HSP70 family and cancer[J].Carcinogene,2013,34(6):1181-1188.
    [6] Bertelsen EB,Chang L,Gestwicki JE,et al.Solution conformation of wild-type E.coli Hsp70(DnaK)chaperone complexed with ADP and substrate[J].Proc Natl Acad Sci U S A,2009,106(21):8471-8476.
    [7] Kevin MF,Camilla DF,David BM.Three-dimensional structure of the ATPase fragment of a 70 K heat-shock cognate protein[J].Nature,1990,346(6285):623-628.
    [8] Powers MV,Jones K,Barillari C,et al.Targeting HSP70:the second potentially druggable heat shock protein and molecular chaperone [J]? Cell Cycle,2010,9(8):1542-1550.
    [9] Wang H,Tan MS,Lu RC,et al.Heat shock proteins at the crossroads between cancer and Alzheimer′s disease[J].Biochem Res Int,2014,2014:239164.
    [10] Kumar S,Stokes J,Singh UP,et al.Targeting Hsp70:a possible therapy for cancer[J].Cancer Lett,2016,374(1):156-166.
    [11] Frydman J.Folding of newly translated proteins in vivo:the role of molecular chaperones[J].Annu Rev Biochem,2001,70(1):603-647.
    [12] Laufen T,Mayer MP,Beisel C,et al.Mechanism of regulation of Hsp70 chaperones by DnaJ cochaperones[J].Proc Natl Acad Sci U S A,1999,96(10):5452-5457.
    [13] Demetrius LA,Simon DK.The inverse association of cancer and Alzheimer′s:a bioenergetic mechanism[J].J R Soc Interface,2013,10(82):20130006.
    [14] Musicco M,Adorni F,Disanto S,et al.Inverse occurrence of cancer and Alzheimer disease:a population-based incidence study[J].Neurology,2013,81(4):322-328.
    [15] Jäättelä M.Over-expression of Hsp70 confers tumorigenicity to mouse fibrosarcoma cells[J].Int J Canc,1995,60(5):689-693.
    [16] Seo JS,Park YM,Kim JI,et al.T cell lymphoma in transgenic mice expressing the human Hsp70 gene[J].Biochem Biophys Res Commun,1996,218(2):582-587.
    [17] Ciocca DR,Calderwood SK.Heat shock proteins in cancer:diagnostic,prognostic,predictive,and treatment implications[J].Cell Stress Chaperones,2005,10(2):86-103.
    [18] Hoozemans JJM,Veerhuis R,Van Haastert ES,et al.The unfolded protein response is activated in Alzheimer′s disease[J].Act Neurop,2005,110(2):165-172.
    [19] Yokota T, Mishra M, Akatsu H, et al. Brain site-specific gene expression analysis in Alzheimer′s disease patients[J].Eur J Clin Invest,2006,36(11):820-830.
    [20] Magrané J,Smith RC,Walsh K,et al.Heat shock protein 70 participates in the neuroprotective response to intracellularly expressed β-amyloid in neurons[J].J Neurosci,2004,24(7):1700-1706.
    [21] Hoshino T,Murao N,Namba T,et al.Suppression of Alzheimer′s disease-related phenotypes by expression of heat shock protein 70 in mice[J].J Neurosci,2011,31(14):5225-5234.
    [22] Evans CG,Wisén S,Gestwicki JE.Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1-42)aggregation in vitro[J].J Biol Chem,2006,,281(44):33182-33191.
    [23] Kumar P,Ambasta RK,Veereshwarayya V,et al.CHIP and HSPs interact with β-APP in a proteasome-dependent manner and influence Aβ metabolism[J].Hum Mol Gen,2007,16(7):848-864.
    [24] Bobkova NV,Evgen′ev M,Garbuz DG,et al.Exogenous Hsp70 delays senescence and improves cognitive function in aging mice[J].Proc Natl Acad Sci U S A,2015,112(52):16006-16011.
    [25] Patterson KR,Ward SM,Combs B,et al.Heat shock protein 70 prevents both tau aggregation and the inhibitory effects of preexisting tau aggregates on fast axonal transport[J].Biochemistry,2011,50(47):10300-10310.
    [26] Jinwal UK,Akoury E,Abisambra JF,et al.Imbalance of Hsp70 family variants fosters tau accumulation[J].FASEB J,2013,27(4):1450-1459.
    [27] Jinwal UK,John CO,Sergiy IB,et al.Hsc70 rapidly engages tau after microtubule destabilization[J].J Biol Chem,2010,285(22):16798-16805.
    [28] Bukau B,Weissman J,Horwich A.Molecular chaperones and protein quality control[J].Cell,2006,125(3):443-451.
    [29] Chang L,Miyata Y,Ung PMU,et al.Chemical screens against a reconstituted multiprotein complex:myricetin blocks DnaJ regulation of DnaK through an allosteric mechanism[J].Chem Biol,2011,18(2):210-221.
    [30] Williams DR,Ko SK,Park S,et al.An apoptosis-inducing small molecule that binds to heat shock protein 70[J].Angew Chem,2008,47(39):7466-7469.
    [31] Baek KH,Zhang H,Lee BR,et al.A small molecule inhibitor for ATPase activity of Hsp70 and Hsc70 enhances the immune response to protein antigens[J].Sci Rep,2015,5:17642.
    [32] Wang AM,Morishima Y,Clapp KM,et al.Inhibition of Hsp70 by methylene blue affects signaling protein function and ubiquitination and modulates polyglutamine protein degradation[J].J Biol Chem,2010,285(21):15714-15723.
    [33] Fewell SW,Day BW,Brodsky JL.Identification of an inhibitor of Hsc70-mediated protein translocation and ATP hydrolysis[J].J Biol Chem,2001,276(2):910-914.
    [34] Fewell SW,Smith CM,Lyon MA,et al.Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity[J].J Biol Chem,2004,279(49):51131-51140.
    [35] Koya K,Li Y,Wang H,et al.MKT-077,a novel rhodacyanine dye in clinical trials,exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation[J].Cancer Res,1996,56(3):538-543.
    [36] Rousaki A,Miyata Y,Jinwal UK,et al.Allosteric drugs:the interaction of antitumor compound MKT-077 with human Hsp70 chaperones[J].J Mol Biol,2011,411(3):614-632.
    [37] Koren IIIJ, Miyata Y, Kiray J, et al. Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance[J].PLoS ONE,2012,7(4):e35566.
    [38] Wang AM, Miyata Y, Klinedinst S, et al. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation[J].Nat Chem Biol,2013,9(2):112-118.
    [39] Abisambra J,Jinwal UK,Miyata Y,et al.Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau[J].Biol Psychiatry,2013,74(5):367-374.
    [40] Miyata Y,Li X,Lee HF,et al.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[J].ACS Chem Neurosci,2013,4(6):930-939.
    [41] Schlecht R,Scholz SR,Dahmen H,et al.Functional analysis of Hsp70 inhibitors[J].PLoS ONE,2013,8(11):e78443.
    [42] Rérole AL,Gobbo J,De Thonel A,et al.Peptides and aptamers targeting HSP70:a novel approach for anticancer chemotherapy[J].Cancer Res,2011,71(2):484-495.
    [43] Strom E,Sathe S,Komarov PG,et al.Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation[J].Nat Chem Biol,2006,2(9):474-479.
    [44] Leu JIJ,Pimkina J,Frank A,et al.A small molecule inhibitor of inducible heat shock protein 70[J].Mol Cell,2009,36(1):15-27.
    [45] Balaburski GM,Julia I,Leu J,et al.A modified HSP70 inhibitor shows broad activity as an anticancer agent[J].Mol Cancer Res,2013,11(3):219-229.
    [46] Kang Y,Taldone T,Patel HJ,et al.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].J Med Chem,2014,57(4):1188-1207.
    [47] Taldone T,Kang Y,Patel HJ,et al.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].J Med Chem,2014,57(4):1208-1224.
    [48] Zeng Y,Cao R,Zhang T,et al.Design and synthesis of piperidine derivatives as novel human heat shock protein 70 inhibitors for the treatment of drug-resistant tumors[J].Eur J Med Chem,2015,97:19-31.
    [49] Ban HS,Naik R,Kim HM,et al.Identification of targets of the HIF-1 inhibitor IDF-11774 using alkyne-conjugated photoaffinity probes[J].Bioconjug Chem,2016,27(8):1911.
    [50] Kim BK,Im JY,Han G,et al.p300 cooperates with c-Jun and PARP-1 at the p300 binding site to activate RhoB transcription in NSC126188-mediated apoptosis[J].Biochim Biophys Acta,2014,1839(5):364-373.
    [51] Victoria AA,Anne T,Jennifer NR,et al.Hsp70 protein complexes as drug targets[J].Curr Pharm Des,2013,19(3):404-417.
    [52] Jinwal UK,Miyata Y,Koren J,et al.Chemical manipulation of Hsp70 ATPase activity regulates tau stability[J].Neurosci,2009,29(39):12079-12088.
    [53] Mohanan A, Deshpande S, Jamadarkhana PG, et al. Delayed intervention in experimental stroke with TRC051384—a small molecule HSP70 inducer[J].Neuropharmacology,2011,60(6):991-999.
    [54] Hoshino T,Suzuki K,Matsushima T,et al.Suppression of Alzheimer′s disease-related phenotypes by geranylgeranylacetone in mice[J].PLoS ONE,2013,8(10):e76306.
    [55] Khodagholi F,Ansari N,Amini M,et al.Involvement of molecular chaperones and the transcription factor Nrf2 in neuroprotection mediated by para-substituted-4,5-diaryl-3-thiomethyl-1,2,4-triazines[J].Cell Stress Chaperones,2012,17(4):409-422.
    [56] Renouf DJ,Hedley D,Krzyzanowska MK,et al.A phase II study of the HSP90 inhibitor AUY922 in chemotherapy refractory advanced pancreatic cancer[J].Cancer Chemother Pharmacol,2016,78(3):541-545.
    [57] Rocio GC,Amancio C,Luis PA.Inhibition of HSP90 molecular chaperones:moving into the clinic[J].Lancet Oncol,2013,14(9):358-369.
计量
  • 文章访问数:  1122
  • HTML全文浏览量:  5
  • PDF下载量:  4039
  • 被引次数: 0
出版历程
  • 刊出日期:  2017-08-24

目录

    /

    返回文章
    返回
    x 关闭 永久关闭