Advertisement

Bioprobes pp 37-74 | Cite as

Epigenetics

Bioprobes that Target Epigenetic Modifications
  • Akihiro ItoEmail author
  • Minoru Yoshida
Chapter
  • 485 Downloads

Abstract

Epigenetics refers to a heritable alteration in gene expression not associated with an alteration in the DNA sequence. In other words, epigenetics is a heritable system that changes the phenotype without changing the genotype. Although the cells that constitute the various organs contain identical genomic DNA sequences, they establish and maintain different terminal phenotypes. This nongenetic cellular memory is based on epigenetics. Epigenetic information is less stable than genetic information, and can be influenced by diverse factors such as age, environment, and stress. Aberrant epigenetic changes are associated with various diseases, including cancers. Epigenetic regulation of gene expression is mediated by histone modifications, such as acetylation and methylation, as well as DNA methylation. These modifications are reversibly modulated by specific enzymes. Therefore, chemical tools that target these epigenetic modulators could not only serve as useful tools for investigating the roles of epigenetics in biological systems and multiple human disorders, but would also have potential as drugs. Indeed, several small molecules that target histone acetylation and DNA methylation have been approved for treatment of cancers. This chapter describes our current knowledge of inhibitors of epigenetic modulators and their clinical development.

Keywords

Cancer DNA methylation Epigenetics Histone acetylation Histone methylation Inhibitor 

References

  1. 1.
    Turner BM (2000) Histone acetylation and an epigenetic code. BioEssays 22(9):836–845. doi: 10.1002/1521-1878(200009)22:9<836::AID-BIES9>3.0.CO;2-X PubMedCrossRefGoogle Scholar
  2. 2.
    Jenuwein T, Allis CD (2001) Translating the histone code. Science 293(5532):1074–1080. doi: 10.1126/science.1063127 PubMedCrossRefGoogle Scholar
  3. 3.
    Baylin SB, Jones PA (2011) A decade of exploring the cancer epigenome—biological and translational implications. Nat Rev Cancer 11(10):726–734. doi: 10.1038/nrc3130 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Ellis L, Atadja PW, Johnstone RW (2009) Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther 8(6):1409–1420. doi: 10.1158/1535-7163.MCT-08-0860 PubMedCrossRefGoogle Scholar
  5. 5.
    Issa JP, Kantarjian HM (2009) Targeting DNA methylation. Clin Cancer Res 15(12):3938–3946. doi: 10.1158/1078-0432.CCR-08-2783 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Yang X, Lay F, Han H, Jones PA (2010) Targeting DNA methylation for epigenetic therapy. Trends Pharmacol Sci 31(11):536–546. doi: 10.1016/j.tips.2010.08.001 PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Wagner JM, Hackanson B, Lubbert M, Jung M (2010) Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenetics 1(3–4):117–136. doi: 10.1007/s13148-010-0012-4 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90(1):85–94. doi: 10.1038/icb.2011.100 PubMedCrossRefGoogle Scholar
  9. 9.
    Rashidi A, Cashen AF (2015) Belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma. Future Oncol 11(11):1659–1664. doi: 10.2217/fon.15.62 PubMedCrossRefGoogle Scholar
  10. 10.
    Laubach JP, Moreau P, San-Miguel JF, Richardson PG (2015) Panobinostat for the treatment of multiple myeloma. Clin Cancer Res 21(21):4767–4773. doi: 10.1158/1078-0432.CCR-15-0530 PubMedCrossRefGoogle Scholar
  11. 11.
    Yang XJ, Seto E (2008) The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 9(3):206–218. doi: 10.1038/nrm2346 PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Khochbin S, Verdel A, Lemercier C, Seigneurin-Berny D (2001) Functional significance of histone deacetylase diversity. Curr Opin Genet Dev 11(2):162–166PubMedCrossRefGoogle Scholar
  13. 13.
    Verdin E, Dequiedt F, Kasler HG (2003) Class II histone deacetylases: versatile regulators. Trends Genet 19(5):286–293. doi: 10.1016/S0168-9525(03)00073-8 PubMedCrossRefGoogle Scholar
  14. 14.
    Yang XJ, Gregoire S (2005) Class II histone deacetylases: from sequence to function, regulation, and clinical implication. Mol Cell Biol 25(8):2873–2884. doi: 10.1128/MCB.25.8.2873-2884.2005 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Verdel A, Curtet S, Brocard MP, Rousseaux S, Lemercier C, Yoshida M, Khochbin S (2000) Active maintenance of mHDA2/mHDAC6 histone-deacetylase in the cytoplasm. Curr Biol 10(12):747–749PubMedCrossRefGoogle Scholar
  16. 16.
    Seigneurin-Berny D, Verdel A, Curtet S, Lemercier C, Garin J, Rousseaux S, Khochbin S (2001) Identification of components of the murine histone deacetylase 6 complex: link between acetylation and ubiquitination signaling pathways. Mol Cell Biol 21(23):8035–8044PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Boyault C, Sadoul K, Pabion M, Khochbin S (2007) HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene 26(37):5468–5476. doi: 10.1128/MCB.21.23.8035-8044.2001 PubMedCrossRefGoogle Scholar
  18. 18.
    Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP (2002) HDAC6 is a microtubule-associated deacetylase. Nature 417(6887):455–458. doi: 10.1038/417455a PubMedCrossRefGoogle Scholar
  19. 19.
    Matsuyama A, Shimazu T, Sumida Y, Saito A, Yoshimatsu Y, Seigneurin-Berny D, Osada H, Komatsu Y, Nishino N, Khochbin S, Horinouchi S, Yoshida M (2002) In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J 21(24):6820–6831PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Guardiola AR, Yao TP (2002) Molecular cloning and characterization of a novel histone deacetylase HDAC10. J Biol Chem 277(5):3350–3356. doi: 10.1074/jbc.M109861200 PubMedCrossRefGoogle Scholar
  21. 21.
    Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401(6749):188–193. doi: 10.1038/43710 PubMedCrossRefGoogle Scholar
  22. 22.
    Shore D, Squire M, Nasmyth KA (1984) Characterization of two genes required for the position-effect control of yeast mating-type genes. EMBO J 3(12):2817–2823PubMedPubMedCentralGoogle Scholar
  23. 23.
    Imai S, Armstrong CM, Kaeberlein M, Guarente L (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403(6771):795–800. doi: 10.1038/35001622 PubMedCrossRefGoogle Scholar
  24. 24.
    Smith JS, Brachmann CB, Celic I, Kenna MA, Muhammad S, Starai VJ, Avalos JL, Escalante-Semerena JC, Grubmeyer C, Wolberger C, Boeke JD (2000) A phylogenetically conserved NAD+−dependent protein deacetylase activity in the Sir2 protein family. Proc Natl Acad Sci U S A 97(12):6658–6663PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Landry J, Slama JT, Sternglanz R (2000) Role of NAD(+) in the deacetylase activity of the SIR2-like proteins. Biochem Biophys Res Commun 278(3):685–690. doi: 10.1006/bbrc.2000.3854 PubMedCrossRefGoogle Scholar
  26. 26.
    Tanner KG, Landry J, Sternglanz R, Denu JM (2000) Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proc Natl Acad Sci U S A 97(26):14178–14182. doi: 10.1073/pnas.250422697 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Sauve AA, Celic I, Avalos J, Deng H, Boeke JD, Schramm VL (2001) Chemistry of gene silencing: the mechanism of NAD+−dependent deacetylation reactions. Biochemistry 40(51):15456–15463PubMedCrossRefGoogle Scholar
  28. 28.
    Jackson MD, Denu JM (2002) Structural identification of 2′- and 3′-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+−dependent histone/protein deacetylases. J Biol Chem 277(21):18535–18544. doi: 10.1074/jbc.M200671200 PubMedCrossRefGoogle Scholar
  29. 29.
    Chang JH, Kim HC, Hwang KY, Lee JW, Jackson SP, Bell SD, Cho Y (2002) Structural basis for the NAD-dependent deacetylase mechanism of Sir2. J Biol Chem 277(37):34489–34498. doi: 10.1074/jbc.M205460200 PubMedCrossRefGoogle Scholar
  30. 30.
    Frye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273(2):793–798. doi: 10.1006/bbrc.2000.3000 PubMedCrossRefGoogle Scholar
  31. 31.
    Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I (2005) Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell 16(10):4623–4635. doi: 10.1091/mbc.E05-01-0033 PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Schwer B, North BJ, Frye RA, Ott M, Verdin E (2002) The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol 158(4):647–657. doi: 10.1083/jcb.200205057 PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP (2002) SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. Proc Natl Acad Sci U S A 99(21):13653–13658. doi: 10.1073/pnas.222538099 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H (2013) SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty acyl lysine. Nature 496(7443):110–113. doi: 10.1038/nature12038 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Feldman JL, Baeza J, Denu JM (2013) Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J Biol Chem 288(43):31350–31356. doi: 10.1074/jbc.C113.511261 PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Teng YB, Jing H, Aramsangtienchai P, He B, Khan S, Hu J, Lin H, Hao Q (2015) Efficient demyristoylase activity of SIRT2 revealed by kinetic and structural studies. Sci Rep 5:8529. doi: 10.1038/srep08529 PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Feldman JL, Dittenhafer-Reed KE, Kudo N, Thelen JN, Ito A, Yoshida M, Denu JM (2015) Kinetic and structural basis for acyl-group selectivity and NAD(+) dependence in sirtuin-catalyzed deacylation. Biochemistry 54(19):3037–3050. doi: 10.1021/acs.biochem.5b00150 PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, Guarente L (2006) SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126(5):941–954. doi: 10.1016/j.cell.2006.06.057 PubMedCrossRefGoogle Scholar
  39. 39.
    Mathias RA, Greco TM, Oberstein A, Budayeva HG, Chakrabarti R, Rowland EA, Kang Y, Shenk T, Cristea IM (2014) Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. Cell 159(7):1615–1625. doi: 10.1016/j.cell.2014.11.046 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Liszt G, Ford E, Kurtev M, Guarente L (2005) Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 280(22):21313–21320. doi: 10.1074/jbc.M413296200 PubMedCrossRefGoogle Scholar
  41. 41.
    Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, He B, Chen W, Zhang S, Cerione RA, Auwerx J, Hao Q, Lin H (2011) Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334(6057):806–809. doi: 10.1126/science.1207861 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Candido EP, Reeves R, Davie JR (1978) Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 14(1):105–113PubMedCrossRefGoogle Scholar
  43. 43.
    Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276(39):36734–36741. doi: 10.1074/jbc.M101287200 PubMedCrossRefGoogle Scholar
  44. 44.
    Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F, Nervi C, Pelicci PG, Heinzel T (2001) Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J 20(24):6969–6978. doi: 10.1093/emboj/20.24.6969 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Bruni J, Wilder BJ (1979) Valproic acid. Review of a new antiepileptic drug. Arch Neurol 36(7):393–398PubMedCrossRefGoogle Scholar
  46. 46.
    Hrebackova J, Hrabeta J, Eckschlager T (2010) Valproic acid in the complex therapy of malignant tumors. Curr Drug Targets 11(3):361–379PubMedCrossRefGoogle Scholar
  47. 47.
    Tassara M, Döhner K, Brossart P, Held G, Götze K, Horst HA, Ringhoffer M, Köhne CH, Kremers S, Raghavachar A, Wulf G, Kirchen H, Nachbaur D, Derigs HG, Wattad M, Koller E, Brugger W, Matzdorff A, Greil R, Heil G, Paschka P, Gaidzik VI, Göttlicher M, Döhner H, Schlenk RF (2014) Valproic acid in combination with all-trans retinoic acid and intensive therapy for acute myeloid leukemia in older patients. Blood 123(26):4027–4036. doi: 10.1182/blood-2013-12-546283 PubMedCrossRefGoogle Scholar
  48. 48.
    Avallone A, Piccirillo MC, Delrio P, Pecori B, Di Gennaro E, Aloj L, Tatangelo F, D’Angelo V, Granata C, Cavalcanti E, Maurea N, Maiolino P, Bianco F, Montano M, Silvestro L, Terranova Barberio M, Roca MS, Di Maio M, Marone P, Botti G, Petrillo A, Daniele G, Lastoria S, Iaffaioli VR, Romano G, Caracò C, Muto P, Gallo C, Perrone F, Budillon A (2014) Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low–moderate risk rectal cancer—V-shoRT-R3 (Valproic Acid–Short Radiotherapy–Rectum 3rd Trial). BMC Cancer 14:875. doi: 10.1186/1471-2407-14-875 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Bilen MA, Fu S, Falchook GS, Ng CS, Wheler JJ, Abdelrahim M, Erguvan-Dogan B, Hong DS, Tsimberidou AM, Kurzrock R, Naing A (2015) Phase I trial of valproic acid and lenalidomide in patients with advanced cancer. Cancer Chemother Pharmacol 75(4):869–874. doi: 10.1007/s00280-015-2695-x PubMedCrossRefGoogle Scholar
  50. 50.
    Krauze AV, Myrehaug SD, Chang MG, Holdford DJ, Smith S, Shih J, Tofilon PJ, Fine HA, Camphausen K (2015) A phase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patients with glioblastoma. Int J Radiat Oncol Biol Phys 92(5):986–992. doi: 10.1016/j.ijrobp.2015.04.038 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Tsuji N, Kobayashi M, Nagashima K, Wakisaka Y, Koizumi K (1976) A new antifungal antibiotic, trichostatin. J Antibioti 29(1):1–6CrossRefGoogle Scholar
  52. 52.
    Yoshida M, Kijima M, Akita M, Beppu T (1990) Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265(28):17174–17179PubMedGoogle Scholar
  53. 53.
    Yoshida M, Beppu T (1988) Reversible arrest of proliferation of rat 3Y1 fibroblasts in both the G1 and G2 phases by trichostatin A. Exp Cell Res 177(1):122–131PubMedCrossRefGoogle Scholar
  54. 54.
    Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA, Marks PA (1998) A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci U S A 95(6):3003–3007PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C, Thaler HT, Rifkind RA, Marks PA, Richon VM (2000) Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60(18):5165–5170PubMedGoogle Scholar
  56. 56.
    Munster PN, Troso-Sandoval T, Rosen N, Rifkind R, Marks PA, Richon VM (2001) The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells. Cancer Res 61(23):8492–8497PubMedGoogle Scholar
  57. 57.
    Cohen LA, Amin S, Marks PA, Rifkind RA, Desai D, Richon VM (1999) Chemoprevention of carcinogen-induced mammary tumorigenesis by the hybrid polar cytodifferentiation agent, suberanilohydroxamic acid (SAHA). Anticancer Res 19(6B):4999–5005PubMedGoogle Scholar
  58. 58.
    He LZ, Tolentino T, Grayson P, Zhong S, Warrell RP Jr, Rifkind RA, Marks PA, Richon VM, Pandolfi PP (2001) Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 108(9):1321–1330. doi: 10.1172/JCI11537 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Marks PA (2007) Discovery and development of SAHA as an anticancer agent. Oncogene 26(9):1351–1356. doi: 10.1038/sj.onc.1210204 PubMedCrossRefGoogle Scholar
  60. 60.
    Lakshmaiah KC, Jacob LA, Aparna S, Lokanatha D, Saldanha SC (2014) Epigenetic therapy of cancer with histone deacetylase inhibitors. J Cancer Res Ther 10(3):469–478. doi: 10.4103/0973-1482.137937 PubMedGoogle Scholar
  61. 61.
    Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci U S A 100(8):4389–4394. doi: 10.1073/pnas.0430973100 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, Luong C, Arvai A, Buggy JJ, Chi E, Tang J, Sang BC, Verner E, Wynands R, Leahy EM, Dougan DR, Snell G, Navre M, Knuth MW, Swanson RV, McRee DE, Tari LW (2004) Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure 12(7):1325–1334. doi: 10.1016/j.str.2004.04.012 PubMedCrossRefGoogle Scholar
  63. 63.
    Vannini A, Volpari C, Filocamo G, Casavola EC, Brunetti M, Renzoni D, Chakravarty P, Paolini C, De Francesco R, Gallinari P, Steinkühler C, Di Marco S (2004) Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor. Proc Natl Acad Sci U S A 101(42):15064–15069. doi: 10.1073/pnas.0404603101 PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Balasubramanian S, Ramos J, Luo W, Sirisawad M, Verner E, Buggy JJ (2008) A novel histone deacetylase 8 (HDAC8)–specific inhibitor PCI-34051 induces apoptosis in T-cell lymphomas. Leukemia 22(5):1026–1034. doi: 10.1038/leu.2008.9 PubMedCrossRefGoogle Scholar
  65. 65.
    Rettig I, Koeneke E, Trippel F, Mueller WC, Burhenne J, Kopp-Schneider A, Fabian J, Schober A, Fernekorn U, von Deimling A, Deubzer HE, Milde T, Witt O, Oehme I (2015) Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid–mediated differentiation. Cell Death Dis 6:e1657. doi: 10.1038/cddis.2015.24 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    el-Beltagi HM, Martens AC, Lelieveld P, Haroun EA, Hagenbeek A (1993) Acetyldinaline: a new oral cytostatic drug with impressive differential activity against leukemic cells and normal stem cells—preclinical studies in a relevant rat model for human acute myelocytic leukemia. Cancer Res 53(13):3008–3014PubMedGoogle Scholar
  67. 67.
    LoRusso PM, Demchik L, Foster B, Knight J, Bissery MC, Polin LM, Leopold WR 3rd, Corbett TH (1996) Preclinical antitumor activity of CI-994. Investig New Drugs 14(4):349–356CrossRefGoogle Scholar
  68. 68.
    Seelig MH, Berger MR (1996) Efficacy of dinaline and its methyl and acetyl derivatives against colorectal cancer in vivo and in vitro. Eur J Cancer 32A(11):1968–1976PubMedCrossRefGoogle Scholar
  69. 69.
    Suzuki T, Ando T, Tsuchiya K, Fukazawa N, Saito A, Mariko Y, Yamashita T, Nakanishi O (1999) Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem 42(15):3001–3003. doi: 10.1021/jm980565u PubMedCrossRefGoogle Scholar
  70. 70.
    Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, Suzuki T, Tsuruo T, Nakanishi O (1999) A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci U S A 96(8):4592–4597PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Jaboin J, Wild J, Hamidi H, Khanna C, Kim CJ, Robey R, Bates SE, Thiele CJ (2002) MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. Cancer Res 62(21):6108–6115PubMedGoogle Scholar
  72. 72.
    Chou CJ, Herman D, Gottesfeld JM (2008) Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. J Biol Chem 283(51):35402–35409. doi: 10.1074/jbc.M807045200 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Bressi JC, Jennings AJ, Skene R, Wu Y, Melkus R, De Jong R, O’Connell S, Grimshaw CE, Navre M, Gangloff AR (2010) Exploration of the HDAC2 foot pocket: synthesis and SAR of substituted N-(2-aminophenyl)benzamides. Bioorg Med Chem Lett 20(10):3142–3145. doi: 10.1016/j.bmcl.2010.03.091 PubMedCrossRefGoogle Scholar
  74. 74.
    Ito T, Umehara T, Sasaki K, Nakamura Y, Nishino N, Terada T, Shirouzu M, Padmanabhan B, Yokoyama S, Ito A, Yoshida M (2011) Real-time imaging of histone H4K12-specific acetylation determines the modes of action of histone deacetylase and bromodomain inhibitors. Chem Biol 18(4):495–507. doi: 10.1016/j.chembiol.2011.02.009 PubMedCrossRefGoogle Scholar
  75. 75.
    Ryan QC, Headlee D, Acharya M, Sparreboom A, Trepel JB, Ye J, Figg WD, Hwang K, Chung EJ, Murgo A, Melillo G, Elsayed Y, Monga M, Kalnitskiy M, Zwiebel J, Sausville EA (2005) Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 23(17):3912–3922. doi: 10.1200/JCO.2005.02.188 PubMedCrossRefGoogle Scholar
  76. 76.
    Gore L, Rothenberg ML, O’Bryant CL, Schultz MK, Sandler AB, Coffin D, McCoy C, Schott A, Scholz C, Eckhardt SG (2008) A phase I and pharmacokinetic study of the oral histone deacetylase inhibitor, MS-275, in patients with refractory solid tumors and lymphomas. Clin Cancer Res 14(14):4517–4525. doi: 10.1158/1078-0432.CCR-07-1461 PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Hauschild A, Trefzer U, Garbe C, Kaehler KC, Ugurel S, Kiecker F, Eigentler T, Krissel H, Schott A, Schadendorf D (2008) Multicenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma. Melanoma Res 18(4):274–278. doi: 10.1097/CMR.0b013e328307c248 PubMedCrossRefGoogle Scholar
  78. 78.
    Kijima M, Yoshida M, Sugita K, Horinouchi S, Beppu T (1993) Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 268(30):22429–22435PubMedGoogle Scholar
  79. 79.
    Taunton J, Hassig CA, Schreiber SL (1996) A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272(5260):408–411PubMedCrossRefGoogle Scholar
  80. 80.
    Furumai R, Komatsu Y, Nishino N, Khochbin S, Yoshida M, Horinouchi S (2001) Potent histone deacetylase inhibitors built from trichostatin A and cyclic tetrapeptide antibiotics including trapoxin. Proc Natl Acad Sci U S A 98(1):87–92. doi: 10.1073/pnas.011405598 PubMedCrossRefGoogle Scholar
  81. 81.
    Komatsu Y, Tomizaki KY, Tsukamoto M, Kato T, Nishino N, Sato S, Yamori T, Tsuruo T, Furumai R, Yoshida M (2001) Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity. Cancer Res 61(11):4459–4466PubMedGoogle Scholar
  82. 82.
    Darkin-Rattray SJ, Gurnett AM, Myers RW, Dulski PM, Crumley TM, Allocco JJ, Cannova C, Meinke PT, Colletti SL, Bednarek MA, Singh SB, Goetz MA, Dombrowski AW, Polishook JD, Schmatz DM (1996) Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proc Natl Acad Sci U S A 93(23):13143–13147PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Nishino N, Jose B, Okamura S, Ebisusaki S, Kato T, Sumida Y, Yoshida M (2003) Cyclic tetrapeptides bearing a sulfhydryl group potently inhibit histone deacetylases. Org Lett 5(26):5079–5082. doi: 10.1021/ol036098e PubMedCrossRefGoogle Scholar
  84. 84.
    Nishino N, Yoshikawa D, Watanabe LA, Kato T, Jose B, Komatsu Y, Sumida Y, Yoshida M (2004) Synthesis and histone deacetylase inhibitory activity of cyclic tetrapeptides containing a retrohydroxamate as zinc ligand. Bioorg Med Chem Lett 14(10):2427–2431. doi: 10.1016/j.bmcl.2004.03.018 PubMedCrossRefGoogle Scholar
  85. 85.
    Jose B, Oniki Y, Kato T, Nishino N, Sumida Y, Yoshida M (2004) Novel histone deacetylase inhibitors: cyclic tetrapeptide with trifluoromethyl and pentafluoroethyl ketones. Bioorg Med Chem Lett 14(21):5343–5346. doi: 10.1016/j.bmcl.2004.08.016 PubMedCrossRefGoogle Scholar
  86. 86.
    Bhuiyan MP, Kato T, Okauchi T, Nishino N, Maeda S, Nishino TG, Yoshida M (2006) Chlamydocin analogs bearing carbonyl group as possible ligand toward zinc atom in histone deacetylases. Bioorg Med Chem 14(10):3438–3446. doi: 10.1016/j.bmc.2005.12.063 PubMedCrossRefGoogle Scholar
  87. 87.
    Arai T, Ashraful Hoque M, Nishino N, Kim HJ, Ito A, Yoshida M (2013) Cyclic tetrapeptides with -SS- bridging between amino acid side chains for potent histone deacetylases’ inhibition. Amino Acids 45(4):835–843. doi: 10.1007/s00726-013-1527-8 PubMedCrossRefGoogle Scholar
  88. 88.
    Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S (1998) FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res 241(1):126–133. doi: 10.1006/excr.1998.4027 PubMedCrossRefGoogle Scholar
  89. 89.
    Furumai R, Matsuyama A, Kobashi N, Lee KH, Nishiyama M, Nakajima H, Tanaka A, Komatsu Y, Nishino N, Yoshida M (2002) FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res 62(17):4916–4921PubMedGoogle Scholar
  90. 90.
    Cole KE, Dowling DP, Boone MA, Phillips AJ, Christianson DW (2011) Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases. J Am Chem Soc 133(32):12474–12477. doi: 10.1021/ja205972n PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Kim D, Lee IS, Jung JH, Yang SI (1999) Psammaplin A, a natural bromotyrosine derivative from a sponge, possesses the antibacterial activity against methicillin-resistant Staphylococcus aureus and the DNA gyrase-inhibitory activity. Arch Pharm Res 22(1):25–29PubMedCrossRefGoogle Scholar
  92. 92.
    Kim D, Lee IS, Jung JH, Lee CO, Choi SU (1999) Psammaplin A, a natural phenolic compound, has inhibitory effect on human topoisomerase II and is cytotoxic to cancer cells. Anticancer Res 19(5B):4085–4090PubMedGoogle Scholar
  93. 93.
    Pina IC, Gautschi JT, Wang GY, Sanders ML, Schmitz FJ, France D, Cornell-Kennon S, Sambucetti LC, Remiszewski SW, Perez LB, Bair KW, Crews P (2003) Psammaplins from the sponge Pseudoceratina purpurea: inhibition of both histone deacetylase and DNA methyltransferase. J Org Chem 68(10):3866–3873. doi: 10.1021/jo034248t PubMedCrossRefGoogle Scholar
  94. 94.
    Nicolaou KC, Hughes R, Pfefferkorn JA, Barluenga S (2001) Optimization and mechanistic studies of psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Chemistry 7(19):4296–4310PubMedCrossRefGoogle Scholar
  95. 95.
    Nicolaou KC, Hughes R, Pfefferkorn JA, Barluenga S, Roecker AJ (2001) Combinatorial synthesis through disulfide exchange: discovery of potent psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA). Chemistry 7(19):4280–4295PubMedCrossRefGoogle Scholar
  96. 96.
    Nian H, Delage B, Ho E, Dashwood RH (2009) Modulation of histone deacetylase activity by dietary isothiocyanates and allyl sulfides: studies with sulforaphane and garlic organosulfur compounds. Environ Mol Mutagen 50(3):213–221. doi: 10.1002/em.20454 PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Myzak MC, Karplus PA, Chung FL, Dashwood RH (2004) A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Res 64(16):5767–5774. doi: 10.1158/0008-5472.CAN-04-1326 PubMedCrossRefGoogle Scholar
  98. 98.
    Tortorella SM, Royce SG, Licciardi PV, Karagiannis TC (2015) Dietary sulforaphane in cancer chemoprevention: the role of epigenetic regulation and HDAC inhibition. Antioxid Redox Signal 22(16):1382–1424. doi: 10.1089/ars.2014.6097 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Wall KA, Klis M, Kornet J, Coyle D, Ame JC, Jacobson MK, Slama JT (1998) Inhibition of the intrinsic NAD+ glycohydrolase activity of CD38 by carbocyclic NAD analogues. Biochem J 335(Pt 3):631–636PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Jackson MD, Schmidt MT, Oppenheimer NJ, Denu JM (2003) Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases. J Biol Chem 278(51):50985–50998. doi: 10.1074/jbc.M306552200 PubMedCrossRefGoogle Scholar
  101. 101.
    Bitterman KJ, Anderson RM, Cohen HY, Latorre-Esteves M, Sinclair DA (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277(47):45099–45107. doi: 10.1074/jbc.M205670200 PubMedCrossRefGoogle Scholar
  102. 102.
    Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W (2001) Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107(2):137–148PubMedCrossRefGoogle Scholar
  103. 103.
    North BJ, Marshall BL, Borra MT, Denu JM, Verdin E (2003) The human Sir2 ortholog, SIRT2, is an NAD+−dependent tubulin deacetylase. Mol Cell 11(2):437–444PubMedCrossRefGoogle Scholar
  104. 104.
    Denu JM (2003) Linking chromatin function with metabolic networks: Sir2 family of NAD(+)-dependent deacetylases. Trends Biochem Sci 28(1):41–48PubMedCrossRefGoogle Scholar
  105. 105.
    Grozinger CM, Chao ED, Blackwell HE, Moazed D, Schreiber SL (2001) Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J Biol Chem 276(42):38837–38843. doi: 10.1074/jbc.M106779200 PubMedCrossRefGoogle Scholar
  106. 106.
    Zhao Y, Dai X, Blackwell HE, Schreiber SL, Chory J (2003) SIR1, an upstream component in auxin signaling identified by chemical genetics. Science 301(5636):1107–1110. doi: 10.1126/science.1084161 PubMedCrossRefGoogle Scholar
  107. 107.
    Mai A, Massa S, Lavu S, Pezzi R, Simeoni S, Ragno R, Mariotti FR, Chiani F, Camilloni G, Sinclair DA (2005) Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/protein deacetylase (sirtuin) inhibitors. J Med Chem 48(24):7789–7795. doi: 10.1021/jm050100l PubMedCrossRefGoogle Scholar
  108. 108.
    Bedalov A, Gatbonton T, Irvine WP, Gottschling DE, Simon JA (2001) Identification of a small molecule inhibitor of Sir2p. Proc Natl Acad Sci U S A 98(26):15113–15118. doi: 10.1073/pnas.261574398 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Neugebauer RC, Uchiechowska U, Meier R, Hruby H, Valkov V, Verdin E, Sippl W, Jung M (2008) Structure–activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode. J Med Chem 51(5):1203–1213. doi: 10.1021/jm700972e PubMedCrossRefGoogle Scholar
  110. 110.
    Heltweg B, Gatbonton T, Schuler AD, Posakony J, Li H, Goehle S, Kollipara R, Depinho RA, Gu Y, Simon JA, Bedalov A (2006) Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res 66(8):4368–4377. doi: 10.1158/0008-5472.CAN-05-3617 PubMedCrossRefGoogle Scholar
  111. 111.
    Napper AD, Hixon J, McDonagh T, Keavey K, Pons JF, Barker J, Yau WT, Amouzegh P, Flegg A, Hamelin E (2005) Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem 48(25):8045–8054. doi: 10.1021/jm050522v PubMedCrossRefGoogle Scholar
  112. 112.
    Solomon JM, Pasupuleti R, Xu L, McDonagh T, Curtis R, DiStefano PS, Huber LJ (2006) Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol 26(1):28–38. doi: 10.1128/MCB.26.1.28-38.2006 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196. doi: 10.1038/nature01960 PubMedCrossRefGoogle Scholar
  114. 114.
    Trapp J, Meier R, Hongwiset D, Kassack MU, Sippl W, Jung M (2007) Structure–activity studies on suramin analogues as inhibitors of NAD+−dependent histone deacetylases (sirtuins). ChemMedChem 2(10):1419–1431. doi: 10.1002/cmdc.200700003 PubMedCrossRefGoogle Scholar
  115. 115.
    Schuetz A, Min J, Antoshenko T, Wang CL, Allali-Hassani A, Dong A, Loppnau P, Vedadi M, Bochkarev A, Sternglanz R, Plotnikov AN (2007) Structural basis of inhibition of the human NAD+−dependent deacetylase SIRT5 by suramin. Structure 15(3):377–389. doi: 10.1016/j.str.2007.02.002 PubMedCrossRefGoogle Scholar
  116. 116.
    Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG (2007) Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 317(5837):516–519. doi: 10.1126/science.1143780 PubMedCrossRefGoogle Scholar
  117. 117.
    Chen X, Wales P, Quinti L, Zuo F, Moniot S, Herisson F, Rauf NA, Wang H, Silverman RB, Ayata C (2015) The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson’s disease but not amyotrophic lateral sclerosis and cerebral ischemia. PLoS One 10(1):e0116919. doi: 10.1371/journal.pone.0116919 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, McCarthy A, Appleyard V, Murray KE, Baker L, Thompson A, Mathers J, Holland SJ, Stark MJ, Pass G, Woods J, Lane DP, Westwood NJ (2008) Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13(5):454–463. doi: 10.1016/j.ccr.2008.03.004 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Yuan H, Wang Z, Li L, Zhang H, Modi H, Horne D, Bhatia R, Chen W (2012) Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 119(8):1904–1914. doi: 10.1182/blood-2011-06-361691 PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Sunami Y, Araki M, Hironaka Y, Morishita S, Kobayashi M, Liew EL, Edahiro Y, Tsutsui M, Ohsaka A, Komatsu N (2013) Inhibition of the NAD-dependent protein deacetylase SIRT2 induces granulocytic differentiation in human leukemia cells. PLoS One 8(2):e57633. doi: 10.1371/journal.pone.0057633 PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Jin Y, Cao Q, Chen C, Du X, Jin B, Pan J (2015) Tenovin-6-mediated inhibition of SIRT1/2 induces apoptosis in acute lymphoblastic leukemia (ALL) cells and eliminates ALL stem/progenitor cells. BMC Cancer 15:226. doi: 10.1186/s12885-015-1282-1 PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, Olah J, Ladwein KI, Schmidtkunz K, Gajer M (2015) Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat Commun 6:6263. doi: 10.1038/ncomms7263 PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Chan HM, La Thangue NB (2001) p300/CBP proteins: HATs for transcriptional bridges and scaffolds. J Cell Sci 114(Pt 13):2363–2373PubMedGoogle Scholar
  124. 124.
    Vetting MW, SdC LP, Yu M, Hegde SS, Magnet S, Roderick SL, Blanchard JS (2005) Structure and functions of the GNAT superfamily of acetyltransferases. Arch Biochem Biophys 433(1):212–226. doi: 10.1016/j.abb.2004.09.003 PubMedCrossRefGoogle Scholar
  125. 125.
    Balasubramanyam K, Varier RA, Altaf M, Swaminathan V, Siddappa NB, Ranga U, Kundu TK (2004) Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem 279(49):51163–51171. doi: 10.1074/jbc.M409024200 PubMedCrossRefGoogle Scholar
  126. 126.
    Balasubramanyam K, Altaf M, Varier RA, Swaminathan V, Ravindran A, Sadhale PP, Kundu TK (2004) Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J Biol Chem 279(32):33716–33726. doi: 10.1074/jbc.M402839200 PubMedCrossRefGoogle Scholar
  127. 127.
    Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, Yamamoto T, Adachi F, Kondo T, Okita K, Asaka I, Aoi T, Watanabe A, Yamada Y, Morizane A, Takahashi J, Ayaki T, Ito H, Yoshikawa K, Yamawaki S, Suzuki S, Watanabe D, Hioki H, Kaneko T, Makioka K, Okamoto K, Takuma H, Tamaoka A, Hasegawa K, Nonaka T, Hasegawa M, Kawata A, Yoshida M, Nakahata T, Takahashi R, Marchetto MC, Gage FH, Yamanaka S, Inoue H (2012) Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med 4(145):145ra104. doi: 10.1126/scitranslmed.3004052 PubMedCrossRefGoogle Scholar
  128. 128.
    Fukuda I, Ito A, Hirai G, Nishimura S, Kawasaki H, Saitoh H, Kimura K, Sodeoka M, Yoshida M (2009) Ginkgolic acid inhibits protein SUMOylation by blocking formation of the E1-SUMO intermediate. Chem Biol 16(2):133–140. doi: 10.1016/j.chembiol.2009.01.009 PubMedCrossRefGoogle Scholar
  129. 129.
    Lau OD, Kundu TK, Soccio RE, Ait-Si-Ali S, Khalil EM, Vassilev A, Wolffe AP, Nakatani Y, Roeder RG, Cole PA (2000) HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol Cell 5(3):589–595PubMedCrossRefGoogle Scholar
  130. 130.
    Cebrat M, Kim CM, Thompson PR, Daugherty M, Cole PA (2003) Synthesis and analysis of potential prodrugs of coenzyme A analogues for the inhibition of the histone acetyltransferase p300. Bioorg Med Chem 11(15):3307–3313PubMedCrossRefGoogle Scholar
  131. 131.
    Liu X, Wang L, Zhao K, Thompson PR, Hwang Y, Marmorstein R, Cole PA (2008) The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451(7180):846–850. doi: 10.1038/nature06546 PubMedCrossRefGoogle Scholar
  132. 132.
    Bowers EM, Yan G, Mukherjee C, Orry A, Wang L, Holbert MA, Crump NT, Hazzalin CA, Liszczak G, Yuan H (2010) Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol 17(5):471–482. doi: 10.1016/j.chembiol.2010.03.006 PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Gao XN, Lin J, Ning QY, Gao L, Yao YS, Zhou JH, Li YH, Wang LL, Yu L (2013) A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells. PLoS One 8(2):e55481. doi: 10.1371/journal.pone.0055481 PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Yan G, Eller MS, Elm C, Larocca CA, Ryu B, Panova IP, Dancy BM, Bowers EM, Meyers D, Lareau L (2013) Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. J Invest Dermatol 133(10):2444–2452. doi: 10.1038/jid.2013.187 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Oike T, Komachi M, Ogiwara H, Amornwichet N, Saitoh Y, Torikai K, Kubo N, Nakano T, Kohno T (2014) C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe. Radiother Oncol 111(2):222–227. doi: 10.1016/j.radonc.2014.03.015 PubMedCrossRefGoogle Scholar
  136. 136.
    Gallenkamp D, Gelato KA, Haendler B, Weinmann H (2014) Bromodomains and their pharmacological inhibitors. ChemMedChem 9(3):438–464. doi: 10.1002/cmdc.201300434 PubMedCrossRefGoogle Scholar
  137. 137.
    Adams-Cioaba MA, Min J (2009) Structure and function of histone methylation binding proteins. Biochem Cell Biol 87(1):93–105. doi: 10.1139/O08-129 PubMedCrossRefGoogle Scholar
  138. 138.
    Eissenberg JC (2012) Structural biology of the chromodomain: form and function. Gene 496(2):69–78. doi: 10.1016/j.gene.2012.01.003 PubMedCrossRefGoogle Scholar
  139. 139.
    Garcia BA, Hake SB, Diaz RL, Kauer M, Morris SA, Recht J, Shabanowitz J, Mishra N, Strahl BD, Allis CD, Hunt DF (2007) Organismal differences in post-translational modifications in histones H3 and H4. J Biol Chem 282(10):7641–7655. doi: 10.1074/jbc.M607900200 PubMedCrossRefGoogle Scholar
  140. 140.
    Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and why. Mol Cell 33(1):1–13. doi: 10.1016/j.molcel.2008.12.013 PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Jenuwein T, Laible G, Dorn R, Reuter G (1998) SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell Mol Life Sci 54(1):80–93PubMedCrossRefGoogle Scholar
  142. 142.
    Singer MS, Kahana A, Wolf AJ, Meisinger LL, Peterson SE, Goggin C, Mahowald M, Gottschling DE (1998) Identification of high-copy disruptors of telomeric silencing in Saccharomyces cerevisiae. Genetics 150(2):613–632PubMedPubMedCentralGoogle Scholar
  143. 143.
    Petrossian TC, Clarke SG (2011) Uncovering the human methyltransferasome. Mol Cell Proteomics 10(1):M110 000976. doi: 10.1074/mcp.M110.000976 PubMedCrossRefGoogle Scholar
  144. 144.
    Dillon SC, Zhang X, Trievel RC, Cheng X (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6(8):227. doi: 10.1186/gb-2005-6-8-227 PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y (2002) Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol 12(12):1052–1058PubMedCrossRefGoogle Scholar
  146. 146.
    McBride AE, Silver PA (2001) State of the arg: protein methylation at arginine comes of age. Cell 106(1):5–8PubMedCrossRefGoogle Scholar
  147. 147.
    Zurita-Lopez CI, Sandberg T, Kelly R, Clarke SG (2012) Human protein arginine methyltransferase 7 (PRMT7) is a type III enzyme forming omega-NG-monomethylated arginine residues. J Biol Chem 287(11):7859–7870. doi: 10.1074/jbc.M111.336271 PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Wei H, Mundade R, Lange KC, Lu T (2014) Protein arginine methylation of non-histone proteins and its role in diseases. Cell Cycle 13(1):32–41. doi: 10.4161/cc.27353 PubMedCrossRefGoogle Scholar
  149. 149.
    Tachibana M, Sugimoto K, Fukushima T, Shinkai Y (2001) Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J Biol Chem 276(27):25309–25317. doi: 10.1074/jbc.M101914200 PubMedCrossRefGoogle Scholar
  150. 150.
    Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev 16(14):1779–1791. doi: 10.1101/gad.989402 PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Casciello F, Windloch K, Gannon F, Lee JS (2015) Functional role of G9a histone methyltransferase in cancer. Front Immunol 6:487. doi: 10.3389/fimmu.2015.00487 PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Greiner D, Bonaldi T, Eskeland R, Roemer E, Imhof A (2005) Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat Chem Biol 1(3):143–145. doi: 10.1038/nchembio721 PubMedCrossRefGoogle Scholar
  153. 153.
    Sun Y, Takada K, Takemoto Y, Yoshida M, Nogi Y, Okada S, Matsunaga S (2012) (2012) Gliotoxin analogues from a marine-derived fungus, Penicillium sp., and their cytotoxic and histone methyltransferase inhibitory activities. J Nat Prod 75(1):111–114. doi: 10.1021/np200740e PubMedCrossRefGoogle Scholar
  154. 154.
    Takahashi M, Takemoto Y, Shimazu T, Kawasaki H, Tachibana M, Shinkai Y, Takagi M, Shin-ya K, Igarashi Y, Ito A, Yoshida M (2012) Inhibition of histone H3K9 methyltransferases by gliotoxin and related epipolythiodioxopiperazines. J Antibiot 65(5):263–265. doi: 10.1038/ja.2012.6 PubMedCrossRefGoogle Scholar
  155. 155.
    Iwasa E, Hamashima Y, Fujishiro S, Higuchi E, Ito A, Yoshida M, Sodeoka M (2010) Total synthesis of (+)-chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. J Am Chem Soc 132(12):4078–4079. doi: 10.1021/ja101280p PubMedCrossRefGoogle Scholar
  156. 156.
    Fujishiro S, Dodo K, Iwasa E, Teng Y, Sohtome Y, Hamashima Y, Ito A, Yoshida M, Sodeoka M (2013) Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: reducing cytotoxicity by structural simplification. Bioorg Med Chem Lett 23(3):733–736. doi: 10.1016/j.bmcl.2012.11.087 PubMedCrossRefGoogle Scholar
  157. 157.
    Kubicek S, O’Sullivan RJ, August EM, Hickey ER, Zhang Q, Teodoro ML, Rea S, Mechtler K, Kowalski JA, Homon CA, Kelly TA, Jenuwein T (2007) Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell 25(3):473–481. doi: 10.1016/j.molcel.2007.01.017 PubMedCrossRefGoogle Scholar
  158. 158.
    Liu F, Chen X, Allali-Hassani A, Quinn AM, Wigle TJ, Wasney GA, Dong A, Senisterra G, Chau I, Siarheyeva A, Norris JL, Kireev DB, Jadhav A, Herold JM, Janzen WP, Arrowsmith CH, Frye SV, Brown PJ, Simeonov A, Vedadi M, Jin J (2010) Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines. J Med Chem 53(15):5844–5857. doi: 10.1021/jm100478y PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Liu F, Barsyte-Lovejoy D, Li F, Xiong Y, Korboukh V, Huang XP, Allali-Hassani A, Janzen WP, Roth BL, Frye SV (2013) Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J Med Chem 56(21):8931–8942. doi: 10.1021/jm401480r PubMedCrossRefGoogle Scholar
  160. 160.
    Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, Ghosh D, Pienta KJ, Sewalt RG, Otte AP, Rubin MA, Chinnaiyan AM (2002) The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419(6907):624–629. doi: 10.1038/nature01075 PubMedCrossRefGoogle Scholar
  161. 161.
    Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM (2003) EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A 100(20):11606–11611. doi: 10.1073/pnas.1933744100 PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Takawa M, Masuda K, Kunizaki M, Daigo Y, Takagi K, Iwai Y, Cho HS, Toyokawa G, Yamane Y, Maejima K, Field HI, Kobayashi T, Akasu T, Sugiyama M, Tsuchiya E, Atomi Y, Ponder BA, Nakamura Y, Hamamoto R (2011) Validation of the histone methyltransferase EZH2 as a therapeutic target for various types of human cancer and as a prognostic marker. Cancer Sci 102(7):1298–12305. doi: 10.1111/j.1349-7006.2011.01958.x PubMedCrossRefGoogle Scholar
  163. 163.
    Aumann S, Abdel-Wahab O (2014) Somatic alterations and dysregulation of epigenetic modifiers in cancers. Biochem Biophys Res Commun 455(1–2):24–34. doi: 10.1016/j.bbrc.2014.08.004 PubMedCrossRefGoogle Scholar
  164. 164.
    Miranda TB, Cortez CC, Yoo CB, Liang G, Abe M, Kelly TK, Marquez VE, Jones PA (2009) DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol Cancer Ther 28(6):1579–1588. doi: 10.1158/1535-7163.MCT-09-0013 CrossRefGoogle Scholar
  165. 165.
    McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, Liu Y, Graves AP, Della Pietra A 3rd, Diaz E, LaFrance LV, Mellinger M, Duquenne C, Tian X, Kruger RG, McHugh CF, Brandt M, Miller WH, Dhanak D, Verma SK, Tummino PJ, Creasy CL (2012) EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2492(7427):108–112. doi: 10.1038/nature11606 CrossRefGoogle Scholar
  166. 166.
    Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, Zeng J, Li M, Fan H, Lin Y (2012) Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A 109(52):21360–21365. doi: 10.1073/pnas.1210371110 PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ, Klaus CR, Sacks JD, Raimondi A, Majer CR, Song J, Scott MP, Jin L, Smith JJ, Olhava EJ, Chesworth R, Moyer MP, Richon VM, Copeland RA, Keilhack H, Pollock RM, Kuntz KW (2012) A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol 8(11):890–896. doi: 10.1038/nchembio.1084 PubMedGoogle Scholar
  168. 168.
    Nasveschuk CG, Gagnon A, Garapaty-Rao S, Balasubramanian S, Campbell R, Lee C, Zhao F, Bergeron L, Cummings R, Trojer P et al (2014) Discovery and optimization of tetramethylpiperidinyl benzamides as inhibitors of EZH2. ACS Med Chem Lett 5(4):378–383. doi: 10.1021/ml400494b PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Daigle SR, Olhava EJ, Therkelsen CA, Majer CR, Sneeringer CJ, Song J, Johnston LD, Scott MP, Smith JJ, Xiao Y, Jin L, Kuntz KW, Chesworth R, Moyer MP, Bernt KM, Tseng JC, Kung AL, Armstrong SA, Copeland RA, Richon VM, Pollock RM (2011) Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20(1):53–65. doi: 10.1016/j.ccr.2011.06.009 PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Daigle SR, Olhava EJ, Therkelsen CA, Basavapathruni A, Jin L, Boriack-Sjodin PA, Allain CJ, Klaus CR, Raimondi A, Scott MP, Waters NJ, Chesworth R, Moyer MP, Copeland RA, Richon VM, Pollock RM (2013) Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122(6):1017–1025. doi: 10.1182/blood-2013-04-497644 PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Hojfeldt JW, Agger K, Helin K (2013) Histone lysine demethylases as targets for anticancer therapy. Nat Rev Drug Discov 12(12):917–930. doi: 10.1038/nrd4154 PubMedCrossRefGoogle Scholar
  172. 172.
    Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, Solleder G, Bastian PJ, Ellinger J, Metzger E, Schüle R, Buettner R (2006) Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence. Cancer Res 66(23):11341–11347. doi: 10.1158/0008-5472.CAN-06-1570 PubMedCrossRefGoogle Scholar
  173. 173.
    Kauffman EC, Robinson BD, Downes MJ, Powell LG, Lee MM, Scherr DS, Gudas LJ, Mongan NP (2011) Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer. Mol Carcinog 50(12):931–944. doi: 10.1002/mc.20758 PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, Field HI, Neal DE, Yamaue H, Ponder BA, Nakamura Y, Hamamoto R (2011) Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer 128(3):574–586. doi: 10.1002/ijc.25349 PubMedCrossRefGoogle Scholar
  175. 175.
    Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, Ciceri F, Blaser JG, Greystoke BF, Jordan AM, Miller CJ, Ogilvie DJ, Somervaille TC (2012) The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21(4):473–487. doi: 10.1016/j.ccr.2012.03.014 PubMedCrossRefGoogle Scholar
  176. 176.
    Lee MG, Wynder C, Schmidt DM, McCafferty DG, Shiekhattar R (2006) Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem Biol 13(6):563–567. doi: 10.1016/j.chembiol.2006.05.004 PubMedCrossRefGoogle Scholar
  177. 177.
    Binda C, Valente S, Romanenghi M, Pilotto S, Cirilli R, Karytinos A, Ciossani G, Botrugno OA, Forneris F, Tardugno M, Edmondson DE, Minucci S, Mattevi A, Mai A (2010) Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J Am Chem Soc 132(19):6827–6833. doi: 10.1021/ja101557k PubMedCrossRefGoogle Scholar
  178. 178.
    Benelkebir H, Hodgkinson C, Duriez PJ, Hayden AL, Bulleid RA, Crabb SJ, Packham G, Ganesan A (2011) Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors. Bioorg Med Chem 19(12):3709–3716. doi: 10.1016/j.bmc.2011.02.017 PubMedCrossRefGoogle Scholar
  179. 179.
    Ueda R, Suzuki T, Mino K, Tsumoto H, Nakagawa H, Hasegawa M, Sasaki R, Mizukami T, Miyata N (2009) Identification of cell-active lysine specific demethylase 1-selective inhibitors. J Am Chem Soc 131(48):17536–17537. doi: 10.1021/ja907055q PubMedCrossRefGoogle Scholar
  180. 180.
    Mimasu S, Umezawa N, Sato S, Higuchi T, Umehara T, Yokoyama S (2010) Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1. Biochemistry 49(30):6494–64503. doi: 10.1021/bi100299r PubMedCrossRefGoogle Scholar
  181. 181.
    Cloos PA, Christensen J, Agger K, Maiolica A, Rappsilber J, Antal T, Hansen KH, Helin K (2006) The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442(7100):307–311. doi: 10.1038/nature04837 PubMedCrossRefGoogle Scholar
  182. 182.
    Hamada S, Kim TD, Suzuki T, Itoh Y, Tsumoto H, Nakagawa H, Janknecht R, Miyata N (2009) Synthesis and activity of N-oxalylglycine and its derivatives as Jumonji C-domain-containing histone lysine demethylase inhibitors. Bioorg Med Chem Lett 19(10):2852–2855. doi: 10.1016/j.bmcl.2009.03.098 PubMedCrossRefGoogle Scholar
  183. 183.
    Maes T, Carceller E, Salas J, Ortega A, Buesa C (2015) Advances in the development of histone lysine demethylase inhibitors. Curr Opin Pharmacol 23:52–60. doi: 10.1016/j.coph.2015.05.009 PubMedCrossRefGoogle Scholar
  184. 184.
    Kruidenier L, Chung CW, Cheng Z, Liddle J, Che K, Joberty G, Bantscheff M, Bountra C, Bridges A, Diallo H, Eberhard D, Hutchinson S, Jones E, Katso R, Leveridge M, Mander PK, Mosley J, Ramirez-Molina C, Rowland P, Schofield CJ, Sheppard RJ, Smith JE, Swales C, Tanner R, Thomas P, Tumber A, Drewes G, Oppermann U, Patel DJ, Lee K, Wilson DM (2012) A selective Jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488(7411):404–408. doi: 10.1038/nature11262 PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Hashizume R, Andor N, Ihara Y, Lerner R, Gan H, Chen X, Fang D, Huang X, Tom MW, Ngo V, Solomon D, Mueller S, Paris PL, Zhang Z, Petritsch C, Gupta N, Waldman TA, James CD (2014) Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat Med 20(12):1394–1396. doi: 10.1038/nm.3716 PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Goll MG, Bestor TH (2005) Eukaryotic cytosine methyltransferases. Annu Rev Biochem 74:481–514. doi: 10.1146/annurev.biochem.74.010904.153721 PubMedCrossRefGoogle Scholar
  187. 187.
    Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324(5929):930–935. doi: 10.1126/science.1170116 PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Kriaucionis S, Heintz N (2009) The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science 324(5929):930–935. doi: 10.1126/science.1170116 CrossRefGoogle Scholar
  189. 189.
    Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466(7310):1129–1133. doi: 10.1038/nature09303 PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Sharma S, Kelly TK, Jones PA (2010) Epigenetics in cancer. Carcinogenesis 31(1):27–36. doi: 10.1093/carcin/bgp220 PubMedCrossRefGoogle Scholar
  191. 191.
    Cheng JC, Matsen CB, Gonzales FA, Ye W, Greer S, Marquez VE, Jones PA, Selker EU (2003) Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J Natl Cancer Inst 95(5):399–409PubMedCrossRefGoogle Scholar
  192. 192.
    Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S, Plass C, Niemeyer CM, Lubbert M (2009) The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia 23(6):1019–1028. doi: 10.1038/leu.2008.397 PubMedCrossRefGoogle Scholar
  193. 193.
    Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P, Tang C, Redkar S, Jones PA (2007) Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res 67(13):6400–6408. doi: 10.1158/0008-5472.CAN-07-0251 PubMedCrossRefGoogle Scholar
  194. 194.
    Chuang JC, Warner SL, Vollmer D, Vankayalapati H, Redkar S, Bearss DJ, Qiu X, Yoo CB, Jones PA (2010) S110, a 5-aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther 9(5):1443–1450. doi: 10.1158/1535-7163.MCT-09-1048 PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Erdmann A, Halby L, Fahy J, Arimondo PB (2015) Targeting DNA methylation with small molecules: what's next? J Med Chem 58(6):2569–2583. doi: 10.1021/jm500843d PubMedCrossRefGoogle Scholar
  196. 196.
    Rilova E, Erdmann A, Gros C, Masson V, Aussagues Y, Poughon-Cassabois V, Rajavelu A, Jeltsch A, Menon Y, Novosad N, Gregoire JM, Vispé S, Schambel P, Ausseil F, Sautel F, Arimondo PB, Cantagrel F (2014) Design, synthesis and biological evaluation of 4-amino-N- (4-aminophenyl)benzamide analogues of quinoline-based SGI-1027 as inhibitors of DNA methylation. ChemMedChem 9(3):590–601. doi: 10.1002/cmdc.201300420 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Japan KK 2017

Authors and Affiliations

  1. 1.Chemical Genetics LaboratoryRIKENWakoJapan
  2. 2.Chemical Genomics Research GroupRIKEN Center for Sustainable Resource ScienceWakoJapan

Personalised recommendations