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PRMT Inhibitors

  • Matthijs J. van Haren
  • Nathaniel I. MartinEmail author
Chapter
  • 27 Downloads
Part of the Topics in Medicinal Chemistry book series (TMC, volume 33)

Abstract

The methylation of arginine residues in numerous protein targets is a post-translational modification that has gained increased interest in the scientific community over the past two decades. Arginine methylation is performed by the dedicated family of protein arginine methyltransferases and is known to be involved in a plethora of cellular pathways and biochemical mechanisms in both healthy and disease states. The development of inhibitors for these enzymes for use as biological tools can lead to a more detailed understanding of the functions of the different members of the PRMT family. In addition, a number of recent studies point towards PRMTs as therapeutic targets for a number of diseases and the first clinical trials with compounds inhibiting PRMTs are now underway. We here provide a broad overview of the current status of the inhibitors that have been developed against PRMTs using both high-throughput screening and rational design approaches.

Keywords

Activity Inhibition Methylation Protein arginine N-methyltransferase Therapeutics 

Abbreviations

aDMA

Asymmetrically dimethylated arginine

AdoHcy

S-adenosyl-l-homocysteine

AdoMet

S-adenosyl-l-methionine

Adox

Adenosine dialdehyde

AMI

Arginine methyltransferase inhibitor

AML

Acute myeloid leukaemia

CARM1

Coactivator-associated arginine methyltransferase

DNA

Deoxyribonucleic acid

EBV

Epstein-Barr virus

EC50

Half maximal effective concentration

GAR

Glycine-arginine rich

HEK293T

Human embryonic kidney cell line

HepG2

Hepatocellular carcinoma cell line

HIV

Human immunodeficiency virus

IC50

Half maximal inhibitory concentration

Ki

Inhibition constant

LNCaP

Lymph node carcinoma of the prostate, prostate cancer cell line

MCF7

Michigan Cancer Foundation-7, breast cancer cell line

MCL

Mantle cell lymphoma

MEP50

Methylosome protein 50

MLL

Mixed lineage leukaemia

MMA

Monomethylated arginine

MTA

Methylthioadenosine

MTAP

5-Methylthioadenosine phosphorylase

PABP1

Poly(A)-binding protein-1

PAD

Protein arginine deiminase

PGM

Proline, glycine, methionine-rich

PK/PD

Pharmacokinetic/pharmacodynamic

PRMT

Protein arginine N-methyltransferase

RNA

Ribonucleic acid

RSF1

Repressor splicing factor

SAH

S-adenosyl-l-homocysteine

SAHH

S-adenosyl-l-homocysteine hydrolase

SAM

S-adenosyl-l-methionine

SAR

Structure-activity relationship

sDMA

Symmetrically dimethylated arginine

SET7

SET domain containing protein 7

SGC

Structural genomics consortium

Tat

Trans-activator of transcription

Notes

Compliance with Ethical Standards

Funding: The support of Leiden University is kindly acknowledged.

Conflict of Interest: Matthijs van Haren declares that he has no conflict of interest. Nathaniel I. Martin declares that he has no conflict of interest.

Ethical Approval: This article does not contain any studies with human participants or animals performed by any of the authors.

References

  1. 1.
    Paik WK, Kim S (1967) Enzymatic methylation of protein fractions from calf thymus nuclei. Biochem Biophys Res Commun 29:14–20CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Paik WK, Kim S (1968) Protein methylase I. Purification and properties of the enzyme. J Biol Chem 243:2108–2114PubMedPubMedCentralGoogle Scholar
  3. 3.
    Boffa LC et al (1977) Distribution of NG, NG,-dimethylarginine in nuclear protein fractions. Biochem Biophys Res Commun 74:969–976CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lee HW et al (1977) S-adenosylmethionine: protein-arginine methyltransferase. Purification and mechanism of the enzyme. Biochemistry 16:78–85CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ghosh SK et al (1988) Purification and molecular identification of two protein methylases I from calf brain. Myelin basic protein- and histone-specific enzyme. J Biol Chem 263:19024–19033PubMedPubMedCentralGoogle Scholar
  6. 6.
    Najbauer J et al (1993) Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. J Biol Chem 268:10501–10509PubMedPubMedCentralGoogle Scholar
  7. 7.
    Rajpurohit R et al (1994) Enzymatic methylation of recombinant heterogeneous nuclear RNP protein A1. Dual substrate specificity for S-adenosylmethionine:histone-arginine N-methyltransferase. J Biol Chem 269:1075–1082PubMedPubMedCentralGoogle Scholar
  8. 8.
    Liu Q, Dreyfuss G (1995) In vivo and in vitro arginine methylation of RNA-binding proteins. Mol Cell Biol 15:2800–2808CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lin WJ et al (1996) The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J Biol Chem 271:15034–15044CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Scott HS et al (1998) Identification and characterization of two putative human arginine methyltransferases (HRMT1L1 and HRMT1L2). Genomics 48:330–340CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Tang J et al (1998) PRMT 3, a type I protein arginine N-methyltransferase that differs from PRMT1 in its oligomerization, subcellular localization, substrate specificity, and regulation. J Biol Chem 273:16935–16945CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Chen D (1999) Regulation of transcription by a protein methyltransferase. Science 284:2174–2177CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Branscombe TL et al (2001) PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins. J Biol Chem 276:32971–32976CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Frankel A et al (2002) The novel human protein arginine N-methyltransferase PRMT6 is a nuclear enzyme displaying unique substrate specificity. J Biol Chem 277:3537–3543CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lee JH et al (2005) PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J Biol Chem 280:3656–3664CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Miranda TB et al (2004) PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity. J Biol Chem 279:22902–22907CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lee J et al (2005) PRMT8, a new membrane-bound tissue-specific member of the protein arginine methyltransferase family. J Biol Chem 280:32890–32896CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cook JR et al (2006) FBXO11/PRMT9, a new protein arginine methyltransferase, symmetrically dimethylates arginine residues. Biochem Biophys Res Commun 342:472–481CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Thompson PR, Fast W (2006) Histone citrullination by protein arginine deiminase: is arginine methylation a green light or a roadblock? ACS Chem Biol 1:433–441CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chang B et al (2007) JMJD6 is a histone arginine demethylase. Science 318:444–447CrossRefGoogle Scholar
  21. 21.
    Webby CJ et al (2009) Jmjd6 catalyses lysyl-hydroxylation of U2AF65, a protein associated with RNA splicing. Science 325:90–93CrossRefGoogle Scholar
  22. 22.
    Unoki M et al (2013) Lysyl 5-hydroxylation, a novel histone modification, by jumonji domain containing 6 (JMJD6). J Biol Chem 288:6053–6062CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Wang F et al (2014) JMJD6 promotes Colon carcinogenesis through negative regulation of p53 by hydroxylation. PLoS Biol 12:e1001819CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Boeckel J-N et al (2011) Jumonji domain-containing protein 6 (Jmjd6) is required for angiogenic sprouting and regulates splicing of VEGF-receptor 1. Proc Natl Acad Sci U S A 108:3276–3281CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Han G et al (2012) The hydroxylation activity of Jmjd6 is required for its homo-oligomerization. J Cell Biochem 113:1663–1670PubMedPubMedCentralGoogle Scholar
  26. 26.
    Böttger A et al (2015) The oxygenase Jmjd6–a case study in conflicting assignments. Biochem J 468:191–202CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Walport LJ et al (2016) Arginine demethylation is catalysed by a subset of JmjC histone lysine demethylases. Nat Commun 7:11974CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Uhlmann T et al (2012) A method for large-scale identification of protein arginine methylation. Mol Cell Proteomics 11:1489–1499CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sylvestersen KB et al (2014) Proteomic analysis of arginine methylation sites in human cells reveals dynamic regulation during transcriptional arrest. Mol Cell Proteomics 13:2072–2088CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Larsen SC et al (2016) Proteome-wide analysis of arginine monomethylation reveals widespread occurrence in human cells. Sci Signal 9:rs9CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and why. Mol Cell 33:1–13CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yang Y, Bedford MT (2013) Protein arginine methyltransferases and cancer. Nat Rev Cancer 13:37–50CrossRefGoogle Scholar
  33. 33.
    Franceschelli S et al (2013) Biological functional relevance of asymmetric dimethylarginine (ADMA) in cardiovascular disease. Int J Mol Sci 14:24412–24421CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zakrzewicz D, Eickelberg O (2009) From arginine methylation to ADMA: a novel mechanism with therapeutic potential in chronic lung diseases. BMC Pulm Med 9:5CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zakrzewicz D et al (2012) Protein arginine methyltransferases (PRMTs): promising targets for the treatment of pulmonary disorders. Int J Mol Sci 13:12383–12400CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Jeong S-J et al (2006) Coactivator-associated arginine methyltransferase 1 enhances transcriptional activity of the human T-cell Lymphotropic virus type 1 long terminal repeat through direct interaction with tax. J Virol 80:10036–10044CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Xie B et al (2007) Arginine methylation of the human immunodeficiency virus type 1 tat protein by PRMT6 negatively affects tat interactions with both cyclin T1 and the tat transactivation region. J Virol 81:4226–4234 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Alinari L et al (2015) Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood 125:2530–2543CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Cheng D et al (2004) Small molecule regulators of protein arginine methyltransferases. J Biol Chem 279:23892–23899CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Peng C, Wong CC (2017) The story of protein arginine methylation: characterization, regulation, and function. Expert Rev Proteomics 14:157–170CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Kaniskan HÜ et al (2017) Inhibitors of protein methyltransferases and demethylases. Chem Rev 118:989–1068CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Blanc RS, Richard S (2017) Arginine methylation: the coming of age. Mol Cell 65:8–24CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Morettin A et al (2015) Arginine methyltransferases as novel therapeutic targets for breast cancer. Mutagenesis 30:177–189CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Boriack-Sjodin PA, Swinger KK (2016) Protein methyltransferases: a distinct, diverse, and dynamic family of enzymes. Biochemistry 55:1557–1569CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Schapira M, Ferreira de Freitas R (2014) Structural biology and chemistry of protein arginine methyltransferases. Med Chem Commun 5:1779–1788CrossRefGoogle Scholar
  46. 46.
    Scheer S et al (2019) A chemical biology toolbox to study protein methyltransferases and epigenetic signaling. Nat Commun 10:19CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kryukov GV et al (2016) MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351:1214–1218CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Marjon K et al (2016) MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep 15:574–587CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Mavrakis KJ et al (2016) Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351:1208–1213CrossRefGoogle Scholar
  50. 50.
    Eram MS et al (2016) A potent, selective, and cell-active inhibitor of human type I protein arginine methyltransferases. ACS Chem Biol 11:772–781CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Tang J et al (2000) Protein-arginine methyltransferase I, the predominant protein-arginine methyltransferase in cells, interacts with and is regulated by interleukin enhancer-binding factor 3. J Biol Chem 275:19866–19876CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Tang J et al (2000) PRMT1 is the predominant type I protein arginine methyltransferase in mammalian cells. J Biol Chem 275:7723–7730CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Goulet I et al (2007) Alternative splicing yields protein arginine methyltransferase 1 isoforms with distinct activity, substrate specificity, and subcellular localization. J Biol Chem 282:33009–33021CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Dhar S et al (2013) Loss of the major type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs. Sci Rep 3:1311CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Wooderchak WL et al (2008) Substrate profiling of PRMT1 reveals amino acid sequences that extend beyond the “RGG” paradigm. Biochemistry 47:9456–9466CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Wei H et al (2014) Protein arginine methylation of non-histone proteins and its role in diseases. Cell Cycle 13:32–41CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Baldwin RM et al (2012) Alternatively spliced protein arginine methyltransferase 1 isoform PRMT1v2 promotes the survival and invasiveness of breast cancer cells. Cell Cycle 11:4597–4612CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Seligson DB et al (2005) Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435:1262–1266CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Avasarala S et al (2015) PRMT1 is a novel regulator of epithelial-mesenchymal-transition in non-small cell lung cancer. J Biol Chem 290:13479–13489CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Mathioudaki K et al (2008) The PRMT1 gene expression pattern in colon cancer. Br J Cancer 99:2094–2099CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Papadokostopoulou A et al (2009) Colon cancer and protein arginine methyltransferase 1 gene expression. Anticancer Res 29:1361–1366PubMedPubMedCentralGoogle Scholar
  62. 62.
    Chuang C et al (2017) PRMT1 expression is elevated in head and neck cancer and inhibition of protein arginine methylation by adenosine dialdehyde or PRMT1 knockdown downregulates proliferation and migration of oral cancer cells. Oncol Rep 38:1115–1123CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Yoshimatsu M et al (2011) Dysregulation of PRMT1 and PRMT6, type I arginine methyltransferases, is involved in various types of human cancers. Int J Cancer 128:562–573CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Cheung N et al (2007) Protein arginine-methyltransferase-dependent oncogenesis. Nat Cell Biol 9:1208–1215CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Shia W-J et al (2012) PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential. Blood 119:4953–4962CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Sun Q et al (2015) PRMT1 upregulated by epithelial Proinflammatory cytokines participates in COX2 expression in fibroblasts and chronic antigen-induced pulmonary inflammation. J Immunol 195:298–306CrossRefGoogle Scholar
  67. 67.
    Iwasaki H (2009) Impaired PRMT1 activity in the liver and pancreas of type 2 diabetic Goto-Kakizaki rats. Life Sci 85:161–166CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Li Y et al (2015) Arginine methyltransferase 1 in the nucleus Accumbens regulates behavioral effects of cocaine. J Neurosci 35:12890–12902CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Ragno R et al (2007) Small molecule inhibitors of histone arginine methyltransferases: homology modeling, molecular docking, binding mode analysis, and biological evaluations. J Med Chem 50:1241–1253CrossRefGoogle Scholar
  70. 70.
    Mai A et al (2008) Epigenetic multiple ligands: mixed histone/protein methyltransferase, acetyltransferase, and class III deacetylase (Sirtuin) inhibitors. J Med Chem 51:2279–2290CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Feng Y et al (2010) Discovery and mechanistic study of a class of protein arginine methylation inhibitors. J Med Chem 53:6028–6039CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Wang J et al (2012) Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation. J Med Chem 55:7978–7987CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Bonham K et al (2010) Effects of a novel arginine methyltransferase inhibitor on T-helper cell cytokine production. FEBS J 277:2096–2108CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Spannhoff A et al (2007) Target-based approach to inhibitors of histone arginine methyltransferases. J Med Chem 50:2319–2325CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Bissinger E-M et al (2011) Acyl derivatives of p-aminosulfonamides and dapsone as new inhibitors of the arginine methyltransferase hPRMT1. Bioorg Med Chem 19:3717–3731CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Spannhoff A et al (2007) A novel arginine methyltransferase inhibitor with cellular activity. Bioorg Med Chem Lett 17:4150–4153CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Heinke R et al (2009) Virtual screening and biological characterization of novel histone arginine methyltransferase PRMT1 inhibitors. ChemMedChem 4:69–77CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Xie Y et al (2014) Virtual screening and biological evaluation of novel small molecular inhibitors against protein arginine methyltransferase 1 (PRMT1). Org Biomol Chem 12:9665–9673CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Dowden J et al (2010) Toward the development of potent and selective bisubstrate inhibitors of protein arginine methyltransferases. Bioorg Med Chem Lett 20:2103–2105CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Dowden J et al (2011) Small molecule inhibitors that discriminate between protein arginine N-methyltransferases PRMT1 and CARM1. Org Biomol Chem 9:7814CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Lakowski TM et al (2010) Nη-substituted Arginyl peptide inhibitors of protein arginine N-methyltransferases. ACS Chem Biol 5:1053–1063CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    ’t Hart P et al (2011) Peptidic partial bisubstrates as inhibitors of the protein arginine N-methyltransferases. Chembiochem 12:1427–1432CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    ’t Hart P et al (2012) Analogues of the HIV-Tat peptide containing Nη-modified arginines as potent inhibitors of protein arginine N-methyltransferases. Med Chem Commun 3:1235–1244CrossRefGoogle Scholar
  84. 84.
    Thomas D et al (2014) Protein arginine N-methyltransferase substrate preferences for different Nη-substituted Arginyl peptides. Chembiochem 15:1607–1613CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Osborne T et al (2008) In situ generation of a Bisubstrate analogue for protein arginine methyltransferase 1. J Am Chem Soc 130:4574–4575CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Luo Y et al (2006) Inhibitors and inactivators of protein arginine deiminase 4: functional and structural characterization. Biochemistry 45:11727–11736CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Obianyo O et al (2010) A chloroacetamidine-based inactivator of protein arginine methyltransferase 1: design, synthesis, and in vitro and in vivo evaluation. Chembiochem 11:1219–1223CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Obianyo O et al (2011) Activity-based protein profiling of protein arginine methyltransferase 1. ACS ChemBio 6:1127–1135CrossRefGoogle Scholar
  89. 89.
    Weerapana E et al (2010) Quantitative reactivity profiling predicts functional cysteines in proteomes. Nature 468:790–795CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Zhang X, Cheng X (2003) Structure of the predominant protein arginine methyltransferase PRMT1 and analysis of its binding to substrate peptides. Structure 11:509–520CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Dillon MBC et al (2012) Novel inhibitors for PRMT1 discovered by high-throughput screening using activity-based fluorescence polarization. ACS Chem Biol 7:1198–1204CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Yan L et al (2014) Diamidine compounds for selective inhibition of protein arginine methyltransferase 1. J Med Chem 57:2611–2622CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Zhang J et al (2017) Discovery of decamidine as a new and potent PRMT1 inhibitor. Med Chem Commun 8:440–444CrossRefGoogle Scholar
  94. 94.
    Sinha SH et al (2012) Synthesis and evaluation of carbocyanine dyes as PRMT inhibitors and imaging agents. Eur J Med Chem 54:647–659CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Hu H et al (2015) Exploration of cyanine compounds as selective inhibitors of protein arginine methyltransferases: synthesis and biological evaluation. J Med Chem 58:1228–1243CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Yu XR et al (2015) Discovery and structure-activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors. Bioorg Med Chem Lett 25:5449–5453CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Lakowski TM, Frankel A (2009) Kinetic analysis of human protein arginine N-methyltransferase 2: formation of monomethyl- and asymmetric dimethyl-arginine residues on histone H4. Biochem J 421:253–261CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Cura V et al (2017) Structural studies of protein arginine methyltransferase 2 reveal its interactions with potential substrates and inhibitors. FEBS J 284:77–96CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Qi C (2002) Identification of protein arginine methyltransferase 2 as a coactivator for estrogen receptor alpha. J Biol Chem 277:28624–28630CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Meyer R et al (2007) PRMT2, a member of the protein arginine methyltransferase family, is a coactivator of the androgen receptor. J Steroid Biochem Mol Biol 107:1–14CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Vhuiyan MI et al (2017) PRMT2 interacts with splicing factors and regulates the alternative splicing of BCL-X. J Biochem 162:17–25PubMedPubMedCentralGoogle Scholar
  102. 102.
    Iwasaki H et al (2010) Disruption of protein arginine N-methyltransferase 2 regulates leptin signaling and produces leanness in vivo through loss of STAT3 methylation. Circ Res 107:992–1001CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Hussein MA et al (2015) LXR-mediated ABCA1 expression and function are modulated by high glucose and PRMT2. PLoS One 10:6–8Google Scholar
  104. 104.
    Zhong J et al (2014) Nuclear loss of protein arginine N-methyltransferase 2 in breast carcinoma is associated with tumor grade and overexpression of cyclin D1 protein. Oncogene 33:5546–5558CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Oh TG et al (2014) PRMT2 and RORγ expression are associated with breast cancer survival outcomes. Mol Endocrinol 28:1166–1185CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    van Haren M et al (2015) Synthesis and evaluation of protein arginine N-methyltransferase inhibitors designed to simultaneously occupy both substrate binding sites. Org Biomol Chem 13:549–560CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Zhang X et al (2000) Crystal structure of the conserved core of protein arginine methyltransferase PRMT3. EMBO J 19:3509–3519CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Frankel A, Clarke S (2000) PRMT3 is a distinct member of the protein arginine N-methyltransferase family: conferral of substrate specificity by a zinc-finger domain. J Biol Chem 275:32974–32982CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Guo H et al (2014) Profiling substrates of protein arginine N-methyltransferase 3 with S-adenosyl-L-methionine analogues. ACS Chem Biol 9:476–484CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Singh V et al (2004) DAL-1/4.1B tumor suppressor interacts with protein arginine N-methyltransferase 3 (PRMT3) and inhibits its ability to methylate substrates in vitro and in vivo. Oncogene 23:7761–7771CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Siarheyeva A et al (2012) An allosteric inhibitor of protein arginine methyltransferase 3. Structure 20:1425–1435CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Liu F et al (2013) Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. J Med Chem 56:2110–2124CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Kaniskan HÜ et al (2015) A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3). Angew Chem Int Ed 54:5166–5170CrossRefGoogle Scholar
  114. 114.
    Lee J (2002) PABP1 identified as an arginine methyltransferase substrate using high-density protein arrays. EMBO Rep 3:268–273CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Cheng D et al (2007) The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Mol Cell 25:71–83CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Schurter BT et al (2001) Methylation of histone H3 by coactivator-associated arginine methyltransferase 1. Biochemistry 40:5747–5756CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Jacques SL et al (2016) CARM1 preferentially methylates H3R17 over H3R26 through a random kinetic mechanism. Biochemistry 55:1635–1644CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Casadio F et al (2013) H3R42me2a is a histone modification with positive transcriptional effects. Proc Natl Acad Sci 110:14894–14899CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Feng Q et al (2006) Signaling within a coactivator complex: methylation of SRC-3/AIB1 is a molecular switch for complex disassembly. Mol Cell Biol 26:7846–7857CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Kuhn P et al (2011) Automethylation of CARM1 allows coupling of transcription and mRNA splicing. Nucleic Acids Res 39:2717–2726CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Daujat S et al (2002) Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Curr Biol 12:2090–2097CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Charoensuksai P et al (2015) O-GlcNAcylation of co-activator-associated arginine methyltransferase 1 regulates its protein substrate specificity. Biochem J 466:587–599CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Cheng H et al (2013) Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. Diagn Pathol 8:129PubMedPubMedCentralGoogle Scholar
  124. 124.
    Kim Y-RR et al (2010) Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer 10:197CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    C-YY O et al (2011) A coactivator role of CARM1 in the dysregulation of -catenin activity in colorectal cancer cell growth and gene expression. Mol Cancer Res 9:660–670CrossRefGoogle Scholar
  126. 126.
    Hong H et al (2004) Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer 101:83–89CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Osada S et al (2013) Elevated expression of coactivator-associated arginine methyltransferase 1 is associated with early hepatocarcinogenesis. Oncol Rep 30:1669–1674CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Purandare AV et al (2008) Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med Chem Lett 18:4438–4441CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Allan M et al (2009) N-Benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1). Bioorg Med Chem Lett 19:1218–1223CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Huynh T et al (2009) Optimization of pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1). Bioorg Med Chem Lett 19:2924–2927CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Wan H et al (2009) Benzo[d]imidazole inhibitors of coactivator associated arginine methyltransferase 1 (CARM1)-hit to Lead studies. Bioorg Med Chem Lett 19:5063–5066CrossRefGoogle Scholar
  132. 132.
    Therrien E et al (2009) 1,2-diamines as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1). Bioorg Med Chem Lett 19:6725–6732CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Sack JS et al (2011) Structural basis for CARM1 inhibition by indole and pyrazole inhibitors. Biochem J 436:331–339CrossRefGoogle Scholar
  134. 134.
    Ferreira De Freitas R et al (2016) Discovery of a potent class i protein arginine methyltransferase fragment inhibitor. J Med Chem 59:1176–1183CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Shen Y et al (2016) Discovery of a potent, selective, and cell-active dual inhibitor of protein arginine methyltransferase 4 and protein arginine methyltransferase 6. J Med Chem 59:9124–9139CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Kaniskan HÜ et al (2016) Design and synthesis of selective, small molecule inhibitors of coactivator-associated arginine methyltransferase 1 (CARM1). Med Chem Commun 7:1793–1796CrossRefGoogle Scholar
  137. 137.
    Nakayama K et al (2018) TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma. Oncotarget 9:18480–18493PubMedPubMedCentralGoogle Scholar
  138. 138.
    Ferreira de Freitas R et al (2016) Discovery of a potent and selective coactivator associated arginine methyltransferase 1 (CARM1) inhibitor by virtual screening. J Med Chem 59:6838–6847CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Cheng DH et al (2011) Novel 3,5-bis(bromohydroxybenzylidene)piperidin-4-ones as coactivator-associated arginine methyltransferase 1 inhibitors: enzyme selectivity and cellular activity. J Med Chem 54:4928–4932CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Selvi BR et al (2010) Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17. J Biol Chem 285:7143–7152CrossRefGoogle Scholar
  141. 141.
    van Haren MJ et al (2017) Transition state mimics are valuable mechanistic probes for structural studies with the arginine methyltransferase CARM1. Proc Natl Acad Sci U S A 114:3625–3630CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Pollack BP et al (1999) The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity. J Biol Chem 274:31531–31542CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Wei H et al (2013) PRMT5 dimethylates R30 of the p65 subunit to activate NF- B. Proc Natl Acad Sci U S A 110:13516–13521CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Migliori V et al (2012) Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance. Nat Struct Mol Biol 19:136–144CrossRefGoogle Scholar
  145. 145.
    Ren J et al (2010) Methylation of ribosomal protein S10 by protein-arginine methyltransferase 5 regulates ribosome biogenesis. J Biol Chem 285:12695–12705CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Jansson M et al (2008) Arginine methylation regulates the p53 response. Nat Cell Biol 10:1431–1439CrossRefGoogle Scholar
  147. 147.
    Zheng S et al (2013) Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1. Mol Cell 52:37–51CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Powers MA et al (2011) Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4. Cancer Res 71:5579–5587CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Andreu-Perez P et al (2011) Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci Signal 4:ra58CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Antonysamy S et al (2012) Crystal structure of the human PRMT5:MEP50 complex. Proc Natl Acad Sci U S A 109:17960–17965CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Ho M-C et al (2013) Structure of the arginine methyltransferase PRMT5-MEP50 reveals a mechanism for substrate specificity. PLoS One 8:e57008CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Morales Y et al (2016) Biochemistry and regulation of the protein arginine methyltransferases (PRMTs). Arch Biochem Biophys 590:138–152CrossRefGoogle Scholar
  153. 153.
    Cho E-C et al (2012) Arginine methylation controls growth regulation by E2F-1. EMBO J 31:1785–1797CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Wei T-YW et al (2012) Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade. Cancer Sci 103:1640–1650CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Győrffy B et al (2013) Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One 8:e82241CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Bao X et al (2013) Overexpression of PRMT5 promotes tumor cell growth and is associated with poor disease prognosis in epithelial ovarian cancer. J Histochem Cytochem 61:206–217CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Pal S et al (2007) Low levels of miR-92b/96 induce PRMT5 translation and H3R8/H4R3 methylation in mantle cell lymphoma. EMBO J 26:3558–3569CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Wang L et al (2008) Protein arginine methyltransferase 5 suppresses the transcription of the RB family of tumor suppressors in leukemia and lymphoma cells. Mol Cell Biol 28:6262–6277CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Chung J et al (2013) Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and Polycomb repressor complex 2 (PRC2) silencing. J Biol Chem 288:35534–35547CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    Nicholas C et al (2013) PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27Kip1. PLoS One 8:e74710CrossRefPubMedPubMedCentralGoogle Scholar
  161. 161.
    Zhang H et al (1996) Codeletion of the genes for p16INK4, methylthioadenosine phosphorylase, interferon-α1, interferon-β1, and other 9p21 markers in human malignant cell lines. Cancer Genet Cytogenet 86:22–28CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Chan-Penebre E et al (2015) A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol 11:432–437CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Duncan KW et al (2016) Structure and property guided design in the identification of PRMT5 tool compound EPZ015666. ACS Med Chem Lett 7:162–166CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Tarighat SS et al (2016) The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation. Leukemia 30:789–799CrossRefGoogle Scholar
  165. 165.
    Gerhart SV et al (2018) Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing. Sci Rep 8:1–15CrossRefGoogle Scholar
  166. 166.
    Bonday ZQ et al (2018) LLY-283, a potent and selective inhibitor of arginine methyltransferase 5, PRMT5, with antitumor activity. ACS Med Chem Lett 9:612–617CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    SGC website: GSK591, a chemical probe for PRMT5. http://www.thesgc.org/chemical-probes/GSK591. Accessed Jan 2019
  168. 168.
    Ji S et al (2016) Discovery of selective protein arginine methyltransferase 5 inhibitors and biological evaluations. Chem Biol Drug Des:585–598Google Scholar
  169. 169.
    Waldmann T et al (2011) Methylation of H2AR29 is a novel repressive PRMT6 target. Epigenetics Chromatin 4:11CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Hyllus D et al (2007) PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation. Genes Dev 21:3369–3380CrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Guccione E et al (2007) Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449:933–937CrossRefGoogle Scholar
  172. 172.
    Sgarra R et al (2006) The AT-hook of the chromatin architectural transcription factor high mobility group A1a is arginine-methylated by protein arginine methyltransferase 6. J Biol Chem 281:3764–3772CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    El-Andaloussi N et al (2006) Arginine methylation regulates DNA polymerase β. Mol Cell 22:51–62CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Boulanger M-C et al (2005) Methylation of tat by PRMT6 regulates human immunodeficiency virus type 1 gene expression. J Virol 79:124–131CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Singhroy DN et al (2013) Automethylation of protein arginine methyltransferase 6 (PRMT6) regulates its stability and its anti-HIV-1 activity. Retrovirology 10:73CrossRefPubMedPubMedCentralGoogle Scholar
  176. 176.
    Vieira FQ et al (2014) Deregulated expression of selected histone methylases and demethylases in prostate carcinoma. Endocr Relat Cancer 21:51–61CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Limm K et al (2013) Deregulation of protein methylation in melanoma. Eur J Cancer 49:1305–1313CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Mitchell LH et al (2015) Aryl Pyrazoles as potent inhibitors of arginine methyltransferases: identification of the first PRMT6 tool compound. ACS Med Chem Lett 6:655–659CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Wu H et al (2016) Structural basis of arginine asymmetrical dimethylation by PRMT6. Biochem J 473:3049–3063CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Feng Y et al (2013) Mammalian protein arginine methyltransferase 7 (PRMT7) specifically targets RXR sites in lysine- and arginine-rich regions. J Biol Chem 288:37010–37025CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Gonsalvez GB et al (2007) Two distinct arginine methyltransferases are required for biogenesis of Sm-class ribonucleoproteins. J Cell Biol 178:733–740CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Debler EW et al (2016) A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase. Proc Natl Acad Sci U S A 113:2068–2073CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Jain K et al (2016) Protein arginine methyltransferase product specificity is mediated by distinct active-site architectures. J Biol Chem 291:18299–18308CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Yao R et al (2014) PRMT7 induces epithelial-to-mesenchymal transition and promotes metastasis in breast cancer. Cancer Res 74:5656–5667CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Baldwin RM et al (2015) Protein arginine methyltransferase 7 promotes breast cancer cell invasion through the induction of MMP9 expression. Oncotarget 6:3013–3032CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Karkhanis V et al (2012) Protein arginine methyltransferase 7 regulates cellular response to DNA damage by methylating promoter histones H2A and H4 of the polymerase δ catalytic subunit gene, POLD1. J Biol Chem 287:29801–29814CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Ferreira TR et al (2014) Altered expression of an RBP-associated arginine methyltransferase 7 in Leishmania major affects parasite infection. Mol Microbiol 94:1085–1102CrossRefGoogle Scholar
  188. 188.
    Gros L et al (2003) Identification of new drug sensitivity genes using genetic suppressor elements: protein arginine N-methyltransferase mediates cell sensitivity to DNA-damaging agents. Cancer Res 63:164–171PubMedPubMedCentralGoogle Scholar
  189. 189.
    Gros L et al (2006) Characterization of prmt7α and β isozymes from Chinese hamster cells sensitive and resistant to topoisomerase II inhibitors. Biochim Biophys Acta 1760:1646–1656CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    Verbiest V et al (2008) Protein arginine (N)-methyl transferase 7 (PRMT7) as a potential target for the sensitization of tumor cells to camptothecins. FEBS Lett 582:1483–1489CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Smil D et al (2015) Discovery of a dual PRMT5-PRMT7 inhibitor. ACS Med Chem Lett 6:408–412CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Sayegh J et al (2007) Regulation of protein arginine methyltransferase 8 (PRMT8) activity by its N-terminal domain. J Biol Chem 282:36444–36453CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Kousaka A et al (2009) The distribution and characterization of endogenous protein arginine N-methyltransferase 8 in mouse CNS. Neuroscience 163:1146–1157CrossRefPubMedPubMedCentralGoogle Scholar
  194. 194.
    Hernandez S, Dominko T (2016) Novel protein arginine methyltransferase 8 isoform is essential for cell proliferation. J Cell Biochem 117:2056–2066CrossRefPubMedPubMedCentralGoogle Scholar
  195. 195.
    Scaramuzzino C et al (2013) Protein arginine methyltransferase 1 and 8 interact with FUS to modify its sub-cellular distribution and toxicity in vitro and in vivo. PLoS One 8:e61576CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Hernandez SJ et al (2017) PRMT8 demonstrates variant-specific expression in cancer cells and correlates with patient survival in breast, ovarian and gastric cancer. Oncol Lett 13:1983–1989CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Yang Y et al (2015) PRMT9 is a type II methyltransferase that methylates the splicing factor SAP145. Nat Commun 6:6428CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Gayatri S et al (2016) Using oriented peptide array libraries to evaluate methylarginine-specific antibodies and arginine methyltransferase substrate motifs. Sci Rep 6:28718CrossRefPubMedPubMedCentralGoogle Scholar
  199. 199.
    ClinicalTrials.gov ID: NCT02783300. A phase I, open-label, dose escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK3326595 in subjects with solid tumors and non-Hodgkin’s Lymp. Accessed Jan 2019Google Scholar

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© Springer Nature Switzerland AG  2019

Authors and Affiliations

  1. 1.Biological Chemistry Group, Institute of Biology LeidenLeiden UniversityLeidenThe Netherlands

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