组蛋白去乙酰化酶8选择性抑制剂的研究进展

钮家琪; 朱雍; 赵爽; 汤啸天; 张智敏; 陆涛

doi:10.11665/j.issn.1000-5048.20160301

组蛋白去乙酰化酶8选择性抑制剂的研究进展

中国药科大学理学院

基金项目: 国家自然科学基金资助项目(No.81202410)；国家教育部博士点基金资助项目(No.20120096120010)

计量
- 文章访问数: 1710
- HTML全文浏览量: 3
- PDF下载量: 3076
出版历程
- 刊出日期: 2016-06-24

Advances in histone deacetylase 8 selective inhibitors

摘要

摘要: 组蛋白去乙酰化酶8(HDAC8)属于Ⅰ类锌离子依赖性的组蛋白去乙酰化酶，与人类病理生理学密切相关。HDAC8参与体内多种关键信号通路，是多种疾病的治疗靶点。随着对HDAC8晶体结构研究的不断深入，多种结构类型的HDAC8抑制剂被报道，主要分为苯基氧肟酸类、吲哚类、邻芳基N-羟基肉桂酰胺类和氮杂环丁酮类等。寻找比泛HDAC抑制剂不良反应小的高效选择性HDAC8抑制剂是目前研究的热点。本文综述了HDAC8的结构、功能及选择性抑制剂的研究进展。
- 组蛋白去乙酰化酶8 /
- 结构 /
- 功能 /
- 选择性抑制剂 /
- 靶点 /
- 抗肿瘤活性 /
- 进展
Abstract: Histone deacetylase 8(HDAC8)is a zinc-dependent class I histone deacetylase, closely related to human pathophysiology. HDAC8 involves in various critical signaling networks and is implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability and parasitic infections. More and more selective HDAC8 inhibitors have been developed based on deepening study of its well-characterized crystal structure. They are mainly divided into several categories such as phenyl hydroxamic acids, indoles, ortho-aryl-N-hydroxycinnamides, azetidinones etc. . Current challenges remain in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Herein, we reviewed the progress in the study of structure and functions of HDAC8 as well as the development of selective HDAC8 inhibitors.
- histone deacetylase 8 /
- structure /
- function /
- selective inhibitor /
- target /
- antitumor activity /
- advance

HTML全文

参考文献(47)

[1]	Haberland M,Montgomery RL,Olson EN.The many roles of histone deacetylases in development and physiology:implications for disease and therapy[J].Nat Rev Genet,2009,10(1):32-42.
[2]	Balasubramanian S,Verner E,Buggy JJ.Isoform-specific histone deacetylase inhibitors:the next step[J]?Cancer Lett,2009,280(2):211-221.
[3]	Chakrabarti A,Oehme I,Witt O,et al.HDAC8:a multifaceted target for therapeutic interventions[J].Trends Pharmacol Sci,2015,36(7):481-492.
[4]	Gregoretti I,Lee YM,Goodson HV.Molecular evolution of the histone deacetylase family:functional implications of phylogenetic analysis[J].J Mol Biol,2004,338(1):17-31.
[5]	Li J,Chen S,Rachel A.Cleary,et al.Histone deacetylase 8 regulates cortactin deacetylation and contraction in smooth muscle tissues[J].Am J Physiol Cell Physiol,2014,307:C288-C295.
[6]	Lee H,Rezai-Zadeh N,Seto E.Negative regulation of histone deacetylase 8 activity by cyclic AMP-dependent protein kinase A[J].Mol Cell Biol,2003,24(2):765-773.
[7]	Deardorff MA,Bando M,Nakato R,et al.HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle[J].Nature,2012,489(7415):313-317.
[8]	Buggy JJ,Dd.MPL,Mcintosh B,et al.Cloning and characterization of a novel human histone deacetylase,HDAC8[J].Biochem J,2000,350:199-205.
[9]	Balasubramanian S, Ramos J, Luo W, et al. A novel histone deacetylase 8(HDAC8)-specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas[J].Leukemia,2008,22(5):1026-1034.
[10]	Scholz C,Weinert BT,Wagner SA,et al.Acetylation site specificities of lysine deacetylase inhibitors in human cells[J].Nat Biotechnol,2015,33(4):415-423.
[11]	Wolfson NA,Pitcairn CA,Fierke CA.HDAC8 substrates:histones and beyond[J].Biopolymers,2013,99(2):112-126.
[12]	Wu J,Du C,Lv Z,et al.The up-regulation of histone deacetylase 8 promotes proliferation and inhibits apoptosis in hepatocellular carcinoma[J].Dig Dis Sci,2013,58(12):3545-3553.
[13]	Wilson BJ,Tremblay AM,Deblois G,et al.An acetylation switch modulates the transcriptional activity of estrogen-related receptor alpha[J].Mol Endocrinol,2010,24(7):1349-1358.
[14]	Olson DE,Udeshi ND,Wolfson NA,et al.An unbiased approach to identify endogenous substrates of "histone" deacetylase 8[J].ACS Chem Biol,2014,9(10):2210-2216.
[15]	Gao J,Siddoway B,Huang Q,et al.Inactivation of CREB mediated gene transcription by HDAC8 bound protein phosphatase[J].Biochem Biophys Res Commun,2009,379(1):1-5.
[16]	Gurard-Levin ZA,Kilian KA,Kim J,et al.Peptide arrays identify isoform selective substrates for profiling endogenous lysine deacetylase activity[J].ACS Chem Biol,2010,5(9):863-873.
[17]	Gurard-Levin ZA,Kim J,Mrksich M.Combining mass spectrometry and peptide arrays to profile the specificities of histone deacetylases[J].Chembiochem,2009,10(13):2159-2161.
[18]	Saha A,Pandian GN,Sato S,et al.Synthesis and biological evaluation of a targeted DNA-binding transcriptional activator with HDAC8 inhibitory activity[J].Bioorg Med Chem,2013,21(14):4201-4209.
[19]	Dose A,Liokatis S,Theillet FX,et al.NMR profiling of histone deacetylase and acetyl-transferase activities in real time[J].ACS Chem Biol,2011,6(5):419-424.
[20]	Gurard-Levin ZA,Mrksich M.The activity of HDAC8 depends on local and distal sequences of its peptide substrates[J].Biochemistry,2008,47(23):6242-6250.
[21]	Kannan S,Melesina J,Hauser AT,et al.Discovery of inhibitors of Schistosoma mansoni HDAC8 by combining homology modeling,virtual screening,and in vitro validation[J].J Chem Inf Model,2014,54(10):3005-3019.
[22]	Nakagawa M,Oda Y,Eguchi T,et al.Expression profile of class I histone deacetylases in human cancer tissues[J].Oncol Rep,2007,18:769-774.
[23]	Oehme I,Deubzer HE,Wegener D,et al.Histone deacetylase 8 in neuroblastoma tumorigenesis[J].Clin Cancer Res,2009,15(1):91-99.
[24]	Vannini A, Volpari C, Filocamo G, et al. Crystal structure of a eukaryotic zinc-dependent histone deacetylase,human HDAC8,complexed with a hydroxamic acid inhibitor[J].Proc Natl Acad Sci U S A,2004,101(42):15064-15069.
[25]	Park SY,Jun JA,Jeong KJ,et al.Histone deacetylases 1,6 and 8 are critical for invasion in breast cancer[J].Oncol Rep,2011,25(6):1677-1681.
[26]	Higuchi T,Nakayama T,Arao T,et al.SOX4 is a direct target gene of FRA-2 andinduces expression of HDAC8 in adult T-cell leukemia/lymphoma[J].Blood,2013,121(18):3640-3649.
[27]	Rettig I,Koeneke E,Trippel F,et al.Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation[J].Cell Death Dis,2015,6:e1657.
[28]	Lee H,Sengupta N,Villagra A,et al.Histone deacetylase 8 safeguards the human ever-shorter telomeres 1B(hEST1B)protein from ubiquitin-mediated degradation[J].Mol Cell Biol,2006,26(14):5259-5269.
[29]	Lutterbach B,Hiebert SW.Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation[J].Gene,2000,245:223-235.
[30]	Durst KL,Lutterbach B,Kummalue T,et al.The inv(16)fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain[J].Mol Cell Biol,2003,23(2):607-619.
[31]	Qian YJ,Zhang J,Jung YS,et al.DEC1 coordinates with HDAC8 to differentially regulate TAp73 and ΔNp73 expression[J].PLoS One,2014,9(1):e84015.
[32]	Gao SM,Chen CQ,Wang LY,et al.Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms[J].Exp Hematol,2013,41(3):261-270.
[33]	Kang Y,Nian H,Rajendran P,et al.HDAC8 and STAT3 repress BMF gene activity in colon cancer cells[J].Cell Death Dis,2014,5:e1476.
[34]	Yan W,Liu S,Xu E,et al.Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8[J].Oncogene,2013,32(5):599-609.
[35]	Marek M, Kannan S, Hauser AT, et al. Structural basis for the inhibition of histone deacetylase 8(HDAC8),a key epigenetic player in the blood fluke Schistosoma mansoni[J].PLoS Pathog,2013,9(9):e1003645.
[36]	Colley DG,Bustinduy AL,Secor WE,et al.Human schistosomiasis[J].The Lancet,2014,383(9936):2253-2264.
[37]	Yamauchi Y,Boukari H,Banerjee I,et al.Histone deacetylase 8 is required for centrosome cohesion and influenza A virus entry[J].PLoS Pathog,2011,7(10):e1002316.
[38]	Van den Wyngaert I,De Vries W,Kremer A,et al.Cloning and characterization of human histone deacetylase 8[J].FEBS Lett,2000,478(1/2):77-83.
[39]	Somoza JR, Skene RJ, Katz BA, et al. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases[J].Structure,2004,12(7):1325-1334.
[40]	Krennhrubec K,Marshall BL,Hedglin M,et al.Design and evaluation of ′Linkerless′ hydroxamic acids as selective HDAC8 inhibitors[J].Bioorg Med Chem Lett,2007,17(10):2874-2878.
[41]	Olson DE,Wagner FF,Kaya T,et al.Discovery of the first histone deacetylase 6/8 dual inhibitors[J].J Med Chem,2013,56(11):4816-4820.
[42]	Tang W,Luo T,Greenberg EF,et al.Discovery of histone deacetylase 8 selective inhibitors[J].Bioorg Med Chem Lett,2011,21(9):2601-2605.
[43]	Suzuki T,Muto N,Bando M,et al.Design,synthesis,and biological activity of NCC149 derivatives as histone deacetylase 8-selective inhibitors[J].ChemMedChem,2014,9(3):657-664.
[44]	Huang WJ, Wang YC, Chao SW, et al. Synthesis and biological evaluation of ortho-aryl-N-hydroxycinnamides as potent histone deacetylase(HDAC)8 isoform-selective inhibitors[J].ChemMedChem,2012,7(10):1815-1824.
[45]	Galletti P,Quintavalla A,Ventrici C,et al.Azetidinones as Zinc-binding groups to design selective HDAC8 inhibitors[J].ChemMedChem,2009,4(12):1991-2001.
[46]	Hu E, Dul E, Sung CM, et al. Identification of novel isoform-selective inhibitors within class I histone deacetylases[J].Pharmacol Exp Ther,2003,307(2):720-728.
[47]	Whitehead L,Dobler MR,Radetich B,et al.Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors[J].Bioorg Med Chem,2011,19(15):4626-4634.

施引文献

资源附件(0)

计量

文章访问数: 1710
HTML全文浏览量: 3
PDF下载量: 3076
被引次数: 0

组蛋白去乙酰化酶8选择性抑制剂的研究进展

计量

出版历程

Advances in histone deacetylase 8 selective inhibitors

计量

出版历程

目录