56. Schermelleh L, Spada F, Easwaran HP et al (2005) Trapped in action: direct visualization of
DNA methyltransferase activity in living cells. Nat Methods 2:751–756. https://doi.org/10.
1038/nmeth794
57. Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects
for epigenetic therapy. Nature 429:457–463. https://doi.org/10.1038/nature02625
58. Rogstad DK, Herring JL, Theruvathu JA et al (2009) Chemical decomposition of 5-aza-20 -deoxycytidine (Decitabine): kinetic analyses and identification of products by NMR, HPLC,
and mass spectrometry. Chem Res Toxicol 22:1194–1204. https://doi.org/10.1021/tx900131u
59. Erdmann A, Halby L, Fahy J, Arimondo PB (2015) Targeting DNA methylation with small
molecules: what’s next? J Med Chem 58:2569–2583. https://doi.org/10.1021/jm500843d
60. Fahy J, Jeltsch A, Arimondo PB (2012) DNA methyltransferase inhibitors in cancer: a
chemical and therapeutic patent overview and selected clinical studies. Expert Opin Ther Pat
22:1427–1442. https://doi.org/10.1517/13543776.2012.729579
61. Agrawal K, Das V, Vyas P, Hajdúch M (2018) Nucleosidic DNA demethylating epigenetic
drugs – a comprehensive review from discovery to clinic. Pharmacol Ther 188:45–79. https://
doi.org/10.1016/J.PHARMTHERA.2018.02.006
62. Chiappinelli KB, Zahnow CA, Ahuja N, Bylin SB (2016) Combining epigenetic and immunotherapy to combat cancer. Cancer Res 76:1683–1689. https://doi.org/10.1158/0008-5472.
CAN-15-2125
63. Hossain MZ, Healey MA, Lee C et al (2013) DNA-intercalators causing rapid re-expression of
methylated and silenced genes in cancer cells. Oncotarget 4:298–309. https://doi.org/10.
18632/oncotarget.863
64. Cherepanova NA, Ivanov AA, Maltseva DV et al (2011) Dimeric bisbenzimidazoles inhibit
the DNA methylation catalyzed by the murine Dnmt3a catalytic domain. J Enzyme Inhib Med
Chem 26:295–300. https://doi.org/10.3109/14756366.2010.499098
65. Zwergel C, Valente S, Mai A (2015) DNA methyltransferases inhibitors from natural sources.
Curr Top Med Chem 16:680–696. https://doi.org/10.2174/1568026615666150825141505
66. Lopez M, Leroy M, Etievant C et al (2016) Drug discovery methods. Drug discovery in cancer
epigenetics. Elsevier, Amsterdam, pp 63–95
67. Song J, Teplova M, Ishibe-Murakami S, Patel DJ (2012) Structure-based mechanistic insights
into DNMT1-mediated maintenance DNA methylation. Science 335:709–712. https://doi.org/
10.1126/science.1214453
68. Siedlecki P, Zielenkiewicz P (2006) Mammalian DNA methyltransferases. Acta Biochim Pol
53:245–256
69. Lin X, Asgari K, Putzi MJ et al (2001) Reversal of GSTP1 CpG island hypermethylation and
reactivation of pi-class glutathione S-transferase (GSTP1) expression in human prostate cancer
cells by treatment with procainamide. Cancer Res 61:8611–8616. https://doi.org/10.1158/
0008-5472.can-04-2957
70. Suzuki T, Tanaka R, Hamada S et al (2010) Design, synthesis, inhibitory activity, and binding
mode study of novel DNA methyltransferase 1 inhibitors. Bioorg Med Chem Lett
20:1124–1127. https://doi.org/10.1016/J.BMCL.2009.12.016
71. Asgatay S, Champion C, Marloie G et al (2014) Synthesis and evaluation of analogues of Nphthaloyl-l-tryptophan (RG108) as inhibitors of DNA methyltransferase 1. J Med Chem
57:421–434. https://doi.org/10.1021/jm401419p
72. Penter L, Maier B, Frede U et al (2015) A rapid screening system evaluates novel inhibitors of
DNA methylation and suggests F-box proteins as potential therapeutic targets for high-risk
neuroblastoma. Target Oncol 10:523–533. https://doi.org/10.1007/s11523-014-0354-5
73. Stresemann C, Brueckner B, Musch T et al (2006) Functional diversity of DNA
methyltransferase inhibitors in human cancer cell lines. Cancer Res 66:2794–2800. https://
doi.org/10.1158/0008-5472.CAN-05-2821
74. Graça I, Sousa EJ, Baptista T et al (2014) Anti-tumoral effect of the non-nucleoside DNMT
inhibitor RG108 in human prostate cancer cells. Curr Pharm Des 20:1803–1811
Chemical Compounds Targeting DNA Methylation and Hydroxymethylation
281
DNA methyltransferase activity in living cells. Nat Methods 2:751–756. https://doi.org/10.
1038/nmeth794
57. Egger G, Liang G, Aparicio A, Jones PA (2004) Epigenetics in human disease and prospects
for epigenetic therapy. Nature 429:457–463. https://doi.org/10.1038/nature02625
58. Rogstad DK, Herring JL, Theruvathu JA et al (2009) Chemical decomposition of 5-aza-20 -deoxycytidine (Decitabine): kinetic analyses and identification of products by NMR, HPLC,
and mass spectrometry. Chem Res Toxicol 22:1194–1204. https://doi.org/10.1021/tx900131u
59. Erdmann A, Halby L, Fahy J, Arimondo PB (2015) Targeting DNA methylation with small
molecules: what’s next? J Med Chem 58:2569–2583. https://doi.org/10.1021/jm500843d
60. Fahy J, Jeltsch A, Arimondo PB (2012) DNA methyltransferase inhibitors in cancer: a
chemical and therapeutic patent overview and selected clinical studies. Expert Opin Ther Pat
22:1427–1442. https://doi.org/10.1517/13543776.2012.729579
61. Agrawal K, Das V, Vyas P, Hajdúch M (2018) Nucleosidic DNA demethylating epigenetic
drugs – a comprehensive review from discovery to clinic. Pharmacol Ther 188:45–79. https://
doi.org/10.1016/J.PHARMTHERA.2018.02.006
62. Chiappinelli KB, Zahnow CA, Ahuja N, Bylin SB (2016) Combining epigenetic and immunotherapy to combat cancer. Cancer Res 76:1683–1689. https://doi.org/10.1158/0008-5472.
CAN-15-2125
63. Hossain MZ, Healey MA, Lee C et al (2013) DNA-intercalators causing rapid re-expression of
methylated and silenced genes in cancer cells. Oncotarget 4:298–309. https://doi.org/10.
18632/oncotarget.863
64. Cherepanova NA, Ivanov AA, Maltseva DV et al (2011) Dimeric bisbenzimidazoles inhibit
the DNA methylation catalyzed by the murine Dnmt3a catalytic domain. J Enzyme Inhib Med
Chem 26:295–300. https://doi.org/10.3109/14756366.2010.499098
65. Zwergel C, Valente S, Mai A (2015) DNA methyltransferases inhibitors from natural sources.
Curr Top Med Chem 16:680–696. https://doi.org/10.2174/1568026615666150825141505
66. Lopez M, Leroy M, Etievant C et al (2016) Drug discovery methods. Drug discovery in cancer
epigenetics. Elsevier, Amsterdam, pp 63–95
67. Song J, Teplova M, Ishibe-Murakami S, Patel DJ (2012) Structure-based mechanistic insights
into DNMT1-mediated maintenance DNA methylation. Science 335:709–712. https://doi.org/
10.1126/science.1214453
68. Siedlecki P, Zielenkiewicz P (2006) Mammalian DNA methyltransferases. Acta Biochim Pol
53:245–256
69. Lin X, Asgari K, Putzi MJ et al (2001) Reversal of GSTP1 CpG island hypermethylation and
reactivation of pi-class glutathione S-transferase (GSTP1) expression in human prostate cancer
cells by treatment with procainamide. Cancer Res 61:8611–8616. https://doi.org/10.1158/
0008-5472.can-04-2957
70. Suzuki T, Tanaka R, Hamada S et al (2010) Design, synthesis, inhibitory activity, and binding
mode study of novel DNA methyltransferase 1 inhibitors. Bioorg Med Chem Lett
20:1124–1127. https://doi.org/10.1016/J.BMCL.2009.12.016
71. Asgatay S, Champion C, Marloie G et al (2014) Synthesis and evaluation of analogues of Nphthaloyl-l-tryptophan (RG108) as inhibitors of DNA methyltransferase 1. J Med Chem
57:421–434. https://doi.org/10.1021/jm401419p
72. Penter L, Maier B, Frede U et al (2015) A rapid screening system evaluates novel inhibitors of
DNA methylation and suggests F-box proteins as potential therapeutic targets for high-risk
neuroblastoma. Target Oncol 10:523–533. https://doi.org/10.1007/s11523-014-0354-5
73. Stresemann C, Brueckner B, Musch T et al (2006) Functional diversity of DNA
methyltransferase inhibitors in human cancer cell lines. Cancer Res 66:2794–2800. https://
doi.org/10.1158/0008-5472.CAN-05-2821
74. Graça I, Sousa EJ, Baptista T et al (2014) Anti-tumoral effect of the non-nucleoside DNMT
inhibitor RG108 in human prostate cancer cells. Curr Pharm Des 20:1803–1811
Chemical Compounds Targeting DNA Methylation and Hydroxymethylation
281