蛋白质精氨酸甲基转移酶5抑制剂的研究进展
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摘要
DNA甲基化作为一种重要的表观遗传修饰方式,参与调控多种疾病的发生与发展。蛋白精氨酸甲基转移酶5(protein arginine methyltransferases 5,PRMT5)是真核细胞常见的一种催化组蛋白或非组蛋白甲基化修饰的酶,在多种人类恶性肿瘤中均表达上调,研发PRMT5抑制剂可能成为治疗癌症的一个重要途径。本文针对PRMT5的结构特征、肿瘤相关性以及目前报道的抑制剂进行综述,为PRMT5抑制剂的进一步优化奠定基础。
As an important style of epigenetic modification,DNA methylation participate in the occurrence and development of various disease.Protein arginine methyltransferases 5(PRMT5)was a common enzyme catalyzing the methylation of histone and non-histone protein.It has been found to be upregulated in human malignant tumor,indicating the significance of develop PRMT5 inhibitors.We reviewed the structural features and its relationship with tumor of PRMT5,as well as the reported PRMT5 inhibitors,supporting the further optimization of PRMT5 inhibitors.
As an important style of epigenetic modification,DNA methylation participate in the occurrence and development of various disease.Protein arginine methyltransferases 5(PRMT5)was a common enzyme catalyzing the methylation of histone and non-histone protein.It has been found to be upregulated in human malignant tumor,indicating the significance of develop PRMT5 inhibitors.We reviewed the structural features and its relationship with tumor of PRMT5,as well as the reported PRMT5 inhibitors,supporting the further optimization of PRMT5 inhibitors.
引文
[1]Moore LD,Le T,Fan G.DNA methylation and its basic function[J].Neuropsychopharmacology,2013,38(1):23-38.
[2]Stopa N,Krebs JE,Shechter D.The PRMT5 arginine methyltransferase:many roles in development,cancer and beyond[J].Cellular and Molecular Life Sciences,2015,72(11):2041-2059.
[3]Fuhrmann J,Thompson PR.Protein arginine methylation and citrullination in epigenetic regulation[J].ACS Chemical Biol,2016,11(3):654-668.
[4]Krause CD,Yang ZH,Kim YS,et al.Protein arginine methyltransferases:evolution and assessment of their pharmacological and therapeutic potential[J].Pharmacol Ther,2007,113(1):50-87.
[5]Morettin A,Baldwin RM,Cote J.Arginine methyltransferases as novel therapeutic targets for breast cancer[J].Mutagenesis,2015,30(2):177-189.
[6]Schapira M,Ferreira de Freitas R.Structural biology and chemistry of protein arginine methyltransferases[J].Medchemcomm,2014,5(12):1779-1788.
[7]Antonysamy S,Bonday Z,Campbell RM,et al.Crystal structure of the human PRMT5:MEP50 complex[J].Proc Nat Acad Scie USA,2012,109(44):17960-17965.
[8]Ho MC,Wilczek C,Bonanno JB,et al.Structure of the arginine methyltransferase PRMT5-MEP50 reveals a mechanism for substrate specificity[J].Plo S One,2013,8(2):e57008.
[9]Wen J,Min XJ,Zhao L,et al.Research progress of effect and mechanism of protein arginine methyltransferase in tumors[J].J Shanghai Jiaotong University(Medical Science),2017,37(6):843-846.[文君,闵雪洁,赵丽,等.蛋白质精氨酸甲基转移酶在肿瘤中的作用及机制研究进展[J].上海交通大学学报(医学版),2017,37(6):843-846.]
[10]Wei TY,Juan CC,Hisa JY,et al.Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade[J].Cancer Scie,2012,103(9):1640-1650.
[11]Sun GZ,Mao HY,Kong GM.Roles of protein arginine methyltransferase 5 in cancer and its clinical application[J].Chin JCancer Biother,2018,25(05):533-537.[孙国壮,毛海燕,孔桂美.蛋白质精氨酸甲基转移酶5在肿瘤中的作用及其临床应用[J].中国肿瘤生物治疗杂志,2018,25(05):533-537.]
[12]Gu Z,Gao S,Zhang F,et al.Protein arginine methyltransferase 5is essential for growth of lung cancer cells[J].The Biochem J,2012,446(2):235-241.
[13]Yan F,Alinari L,Lustberg ME,et al.Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma[J].Cancer Res,2014,74(6):1752-1765.
[14]Bao X,Zhao S,Liu T,et al.Overexpression of PRMT5 promotes tumor cell growth and is associated with poor disease prognosis in epithelial ovarian cancer[J].J Histochem Cytochem,2013,61(3):206-217.
[15]Han X,Li R,Zhang W,et al.Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro[J].J Neuro-oncol,2014,118(1):61-72.
[16]Zhang HT,Zhang D,Zha ZG,et al.Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells[J].Biochimica et Biophysica Acta,2014,1839(11):1330-1340.
[17]Bao XX,Zhang R,Wang ZC,et al.Effect of PRMT5 on proliferation,migration and invasion of ovarian cancer cells[J].Prog Obstet Gynecol,2018,27(02):90-94.[包香香,张瑞,王子超,等.PRMT5对卵巢癌细胞增殖及侵袭转移能力的影响[J].现代妇产科进展,2018,27(02):90-94.]
[18]Wu Xiaobin,Xu Hongying,Xu Hui.miR-203a-3p inhibits the proliferation of gastric cancer cells by targeting PRMT5[J].Modern Oncology,2017,25(14):2226-2230.[吴晓斌,许红英,徐慧.miR-203a-3p通过靶向PRMT5抑制胃癌细胞增殖[J].现代肿瘤医学,2017,25(14):2226-2230.]
[19]Yang F,Wang J,Ren HY,et al.Proliferative role of TRAF4 in breast cancer by upregulating PRMT5 nuclear expression[J].Tumour Biology,2015,36(8):5901-5911.
[20]Ibrahim R,Matsubara D,Osman W,et al.Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition[J].Human Pathol,2014,45(7):1397-1405.
[21]Kong J,Wang Z,Yang YS,et al.Regulation of PRMT5 on the sensitivity to docetaxel of triple negative breast cancer[J].Progress in Modern Biomedicine,2018,18(06):1050-1054.[孔静,王哲,杨云舒,等.PRMT5调控三阴性乳腺癌对多西他赛敏感性的研究[J].现代生物医学进展,2018,18(06):1050-1054.]
[22]Kanno Y,Inajima J,Kato S,et al.Protein arginine methyltransferase 5(PRMT5)is a novel coactivator of constitutive androstane receptor(CAR)[J].Biochem Biophys Res Commun,2015,459(1):143-147.
[23]Zhang B,Dong S,Li Z,et al.Targeting protein arginine methyltransferase 5 inhibits human hepatocellular carcinoma growth via the downregulation of beta-catenin[J].J Transl Med,2015,13:349.
[24]Tarighat SS,Santhanam R,Frankhouser D,et al.The dual epigenetic role of PRMT5 in acute myeloid leukemia:gene activation and repression via histone arginine methylation[J].Leukemia,2016,30(4):789-799.
[25]Wang L,Pal S,Sif S.Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells[J].Mol Cell Biol,2008,28(20):6262-6277.
[26]Chiang K,Zielinska AE,Shaaban AM,et al.PRMT5 is a critical regulator of breast cancer stem cell function via histone methylation and FOXP1 expression[J].Cell Rep,2017,21(12):3498-3513.
[27]Baldwin RM,Morettin A,Cote J.Role of PRMTs in cancer:Could minor isoforms be leaving a mark[J]?World J Biol Chem,2014,5(2):115-129.
[28]Braun CJ,Stanciu M,Boutz PL,et al.Coordinated splicing of regulatory detained introns within oncogenic transcripts creates an exploitable vulnerability in malignant glioma[J].Cancer Cell,2017,32(4):411-426.
[29]Zakrzewicz D,Didiasova M,Kruger M,et al.Protein arginine methyltransferase 5 mediates enolase-1 cell surface trafficking in human lung adenocarcinoma cells[J].Biochimica et Biophysica Acta,2018,1864(5 Pt A):1816-1827.
[30]Hong W,Wang H.Synthesis of novelprotein arginine methyltransferase 5 inhibitor[J].Chemical Reagents,2012,34(5):454-456.[洪伟,王昊.新型蛋白质精氨酸甲基转移酶抑制剂的合成[J].化学试剂,2012,34(5):454-456.]
[31]Mao R,Shao J,Zhu K,et al.Potent,selective,and cell active protein arginine methyltransferase 5(PRMT5)inhibitor developed by structure-based virtual screening and Hit optimization[J].Cancer,2017,60(14):6289-6304.
[32]Zhu K,Jiang CS,Hu J,et al.Interaction assessments of the first S-adenosylmethionine competitive inhibitor and the essential interacting partner methylosome protein 50 with protein arginine methyltransferase 5 by combined computational methods[J].Biochem Biophys Res Communicat,2018,495(1):721-727.
[33]Ye Y,Zhang B,Mao R,et al.Discovery and optimization of selective inhibitors of protein arginine methyltransferase 5 by dockingbased virtual screening[J].Org Biomol Chem,2017,15(17):3648-3661.
[34]Zhu K,Jiang C,Tao H,et al.Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5(PRMT5)by virtual screening,resynthesis and biological evaluations[J].Bioorg Med Chem Lett,2018,28(9):1476-1483.
[35]Sun L,Wang M,Lv Z,et al.Structural insights into protein arginine symmetric dimethylation by PRMT5[J].Proc Nat Acad Sci USA,2011,108(51):20538-20543.
[36]Alinari L,Mahasenan KV,Yan F,et al.Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation[J].Blood,2015,125(16):2530-2543.
[37]Rioux N,Duncan KW,Lantz RJ,et al.Species differences in metabolism of EPZ015666,an oxetane-containing protein arginine methyltransferase-5(PRMT5)inhibitor[J].Xenobiotica,2016,46(3):268-277.
[38]Duncan KW,Rioux N,Boriack-Sjodin PA,et al.Structure and property guided design in the identification of PRMT5 tool compound EPZ015666[J].ACS Med Chem Lett,2016,7(2):162-166.
[39]Chan-Penebre E,Kuplast KG,Majer CR,et al.A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models[J].Nat Chem Biol,2015,11(6):432-437.
[2]Stopa N,Krebs JE,Shechter D.The PRMT5 arginine methyltransferase:many roles in development,cancer and beyond[J].Cellular and Molecular Life Sciences,2015,72(11):2041-2059.
[3]Fuhrmann J,Thompson PR.Protein arginine methylation and citrullination in epigenetic regulation[J].ACS Chemical Biol,2016,11(3):654-668.
[4]Krause CD,Yang ZH,Kim YS,et al.Protein arginine methyltransferases:evolution and assessment of their pharmacological and therapeutic potential[J].Pharmacol Ther,2007,113(1):50-87.
[5]Morettin A,Baldwin RM,Cote J.Arginine methyltransferases as novel therapeutic targets for breast cancer[J].Mutagenesis,2015,30(2):177-189.
[6]Schapira M,Ferreira de Freitas R.Structural biology and chemistry of protein arginine methyltransferases[J].Medchemcomm,2014,5(12):1779-1788.
[7]Antonysamy S,Bonday Z,Campbell RM,et al.Crystal structure of the human PRMT5:MEP50 complex[J].Proc Nat Acad Scie USA,2012,109(44):17960-17965.
[8]Ho MC,Wilczek C,Bonanno JB,et al.Structure of the arginine methyltransferase PRMT5-MEP50 reveals a mechanism for substrate specificity[J].Plo S One,2013,8(2):e57008.
[9]Wen J,Min XJ,Zhao L,et al.Research progress of effect and mechanism of protein arginine methyltransferase in tumors[J].J Shanghai Jiaotong University(Medical Science),2017,37(6):843-846.[文君,闵雪洁,赵丽,等.蛋白质精氨酸甲基转移酶在肿瘤中的作用及机制研究进展[J].上海交通大学学报(医学版),2017,37(6):843-846.]
[10]Wei TY,Juan CC,Hisa JY,et al.Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade[J].Cancer Scie,2012,103(9):1640-1650.
[11]Sun GZ,Mao HY,Kong GM.Roles of protein arginine methyltransferase 5 in cancer and its clinical application[J].Chin JCancer Biother,2018,25(05):533-537.[孙国壮,毛海燕,孔桂美.蛋白质精氨酸甲基转移酶5在肿瘤中的作用及其临床应用[J].中国肿瘤生物治疗杂志,2018,25(05):533-537.]
[12]Gu Z,Gao S,Zhang F,et al.Protein arginine methyltransferase 5is essential for growth of lung cancer cells[J].The Biochem J,2012,446(2):235-241.
[13]Yan F,Alinari L,Lustberg ME,et al.Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma[J].Cancer Res,2014,74(6):1752-1765.
[14]Bao X,Zhao S,Liu T,et al.Overexpression of PRMT5 promotes tumor cell growth and is associated with poor disease prognosis in epithelial ovarian cancer[J].J Histochem Cytochem,2013,61(3):206-217.
[15]Han X,Li R,Zhang W,et al.Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro[J].J Neuro-oncol,2014,118(1):61-72.
[16]Zhang HT,Zhang D,Zha ZG,et al.Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells[J].Biochimica et Biophysica Acta,2014,1839(11):1330-1340.
[17]Bao XX,Zhang R,Wang ZC,et al.Effect of PRMT5 on proliferation,migration and invasion of ovarian cancer cells[J].Prog Obstet Gynecol,2018,27(02):90-94.[包香香,张瑞,王子超,等.PRMT5对卵巢癌细胞增殖及侵袭转移能力的影响[J].现代妇产科进展,2018,27(02):90-94.]
[18]Wu Xiaobin,Xu Hongying,Xu Hui.miR-203a-3p inhibits the proliferation of gastric cancer cells by targeting PRMT5[J].Modern Oncology,2017,25(14):2226-2230.[吴晓斌,许红英,徐慧.miR-203a-3p通过靶向PRMT5抑制胃癌细胞增殖[J].现代肿瘤医学,2017,25(14):2226-2230.]
[19]Yang F,Wang J,Ren HY,et al.Proliferative role of TRAF4 in breast cancer by upregulating PRMT5 nuclear expression[J].Tumour Biology,2015,36(8):5901-5911.
[20]Ibrahim R,Matsubara D,Osman W,et al.Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition[J].Human Pathol,2014,45(7):1397-1405.
[21]Kong J,Wang Z,Yang YS,et al.Regulation of PRMT5 on the sensitivity to docetaxel of triple negative breast cancer[J].Progress in Modern Biomedicine,2018,18(06):1050-1054.[孔静,王哲,杨云舒,等.PRMT5调控三阴性乳腺癌对多西他赛敏感性的研究[J].现代生物医学进展,2018,18(06):1050-1054.]
[22]Kanno Y,Inajima J,Kato S,et al.Protein arginine methyltransferase 5(PRMT5)is a novel coactivator of constitutive androstane receptor(CAR)[J].Biochem Biophys Res Commun,2015,459(1):143-147.
[23]Zhang B,Dong S,Li Z,et al.Targeting protein arginine methyltransferase 5 inhibits human hepatocellular carcinoma growth via the downregulation of beta-catenin[J].J Transl Med,2015,13:349.
[24]Tarighat SS,Santhanam R,Frankhouser D,et al.The dual epigenetic role of PRMT5 in acute myeloid leukemia:gene activation and repression via histone arginine methylation[J].Leukemia,2016,30(4):789-799.
[25]Wang L,Pal S,Sif S.Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells[J].Mol Cell Biol,2008,28(20):6262-6277.
[26]Chiang K,Zielinska AE,Shaaban AM,et al.PRMT5 is a critical regulator of breast cancer stem cell function via histone methylation and FOXP1 expression[J].Cell Rep,2017,21(12):3498-3513.
[27]Baldwin RM,Morettin A,Cote J.Role of PRMTs in cancer:Could minor isoforms be leaving a mark[J]?World J Biol Chem,2014,5(2):115-129.
[28]Braun CJ,Stanciu M,Boutz PL,et al.Coordinated splicing of regulatory detained introns within oncogenic transcripts creates an exploitable vulnerability in malignant glioma[J].Cancer Cell,2017,32(4):411-426.
[29]Zakrzewicz D,Didiasova M,Kruger M,et al.Protein arginine methyltransferase 5 mediates enolase-1 cell surface trafficking in human lung adenocarcinoma cells[J].Biochimica et Biophysica Acta,2018,1864(5 Pt A):1816-1827.
[30]Hong W,Wang H.Synthesis of novelprotein arginine methyltransferase 5 inhibitor[J].Chemical Reagents,2012,34(5):454-456.[洪伟,王昊.新型蛋白质精氨酸甲基转移酶抑制剂的合成[J].化学试剂,2012,34(5):454-456.]
[31]Mao R,Shao J,Zhu K,et al.Potent,selective,and cell active protein arginine methyltransferase 5(PRMT5)inhibitor developed by structure-based virtual screening and Hit optimization[J].Cancer,2017,60(14):6289-6304.
[32]Zhu K,Jiang CS,Hu J,et al.Interaction assessments of the first S-adenosylmethionine competitive inhibitor and the essential interacting partner methylosome protein 50 with protein arginine methyltransferase 5 by combined computational methods[J].Biochem Biophys Res Communicat,2018,495(1):721-727.
[33]Ye Y,Zhang B,Mao R,et al.Discovery and optimization of selective inhibitors of protein arginine methyltransferase 5 by dockingbased virtual screening[J].Org Biomol Chem,2017,15(17):3648-3661.
[34]Zhu K,Jiang C,Tao H,et al.Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5(PRMT5)by virtual screening,resynthesis and biological evaluations[J].Bioorg Med Chem Lett,2018,28(9):1476-1483.
[35]Sun L,Wang M,Lv Z,et al.Structural insights into protein arginine symmetric dimethylation by PRMT5[J].Proc Nat Acad Sci USA,2011,108(51):20538-20543.
[36]Alinari L,Mahasenan KV,Yan F,et al.Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation[J].Blood,2015,125(16):2530-2543.
[37]Rioux N,Duncan KW,Lantz RJ,et al.Species differences in metabolism of EPZ015666,an oxetane-containing protein arginine methyltransferase-5(PRMT5)inhibitor[J].Xenobiotica,2016,46(3):268-277.
[38]Duncan KW,Rioux N,Boriack-Sjodin PA,et al.Structure and property guided design in the identification of PRMT5 tool compound EPZ015666[J].ACS Med Chem Lett,2016,7(2):162-166.
[39]Chan-Penebre E,Kuplast KG,Majer CR,et al.A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models[J].Nat Chem Biol,2015,11(6):432-437.