Synthesis of lysine methyltransferase inhibitors

Frontiers in Chemistry

Volumn 3, Issue JUL, 2015, Pages

  Hui, Chunngai ^a   Ye, Tao ^a  

^a HONG KONG POLYTECHNIC UNIVERSITY   (Hong Kong)

Author keywords

Epigenetics; Inhibitors; Lysine methyltransferase; S adenosyl l methionine; Synthesis

Indexed keywords

EID: 84969579998     PISSN: None     EISSN: 22962646     Source Type: Journal    
DOI: 10.3389/fchem.2015.00044     Document Type: Review

References (115)

1. Abbas, T., Shibata, E., Park, J., Jha, S., Karnani, N., and Dutta, A. (2010). CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation. Mol. Cell 40, 9-21. doi: 10.1016/j.molcel.2010.09.014
2. Andrus, M. B., Mettath, S. N., and Song, C. (2002). A modified synthesis of Iodoazidoaryl Prazosin. J. Org. Chem. 67, 8284-8286. doi: 10.1021/jo026217o
3. Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K., and Schapira, M. (2012). Epigenetic protein families: a new frontier for drug discovery. Nat. Rev. Drug Discov. 11, 384-400. doi: 10.1038/nrd3674
4. Aurelio, L., Box, J. S., Brownlee, R. T. C., Hughes, A. B., and Sleebs, M. M. (2003). An efficient synthesis of N-methyl amino acids by way of intermediate 5-oxazolidinones. J. Org. Chem. 68, 2652-2667. doi: 10.1021/jo026722l
5. Ayton, P. M., and Cleary, M. L. (2001). Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695-5707. doi: 10.1038/sj.onc.1204639
6. Basavapathruni, A., Jin, L., Daigle, S. R., Majer, C. R. A., Therkelsen, C. A., Wigle, T. J., et al. (2012). Conformational adaptation drives potent, selective and durable inhibition of the human protein Methyltransferase DOT1L. Chem. Biol. Drug Des. 80, 971-980. doi: 10.1111/cbdd.12050
7. Basavapathruni, A., Olhava, E. J., Daigle, S. R., Therkelsen, C. A., Jin, L., Boriack-Sjodin, P. A., et al. (2014). Nonclinical pharmacokinetics and metabolism of EPZ-5676, a novel DOT1L histone methyltransferase inhibitor. Biopharm. Drug Dispos. 35, 237-252. doi: 10.1002/bdd.1889
8. Batcho, A. D., and Leimgruber, W. (1985). Indoles from 2-methylnitrobenzenes by condensation with formamide acetals followed by reduction: 4-benzyloxyindole. Org. Synth. 63, 214-220. doi: 10.15227/orgsyn.063.0214
9. Beck, D. B., Oda, H., Shen, S. S., and Reinberg, D. (2012). PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Gene. Dep. 26, 325-337. doi: 10.1101/gad.177444.111
10. Blum, G., Ibáñez, G., Rao, X., Shum, D., Radu, C., Djaballah, H., et al. (2014). Small-Molecule Inhibitors of SETD8 with Cellular Activity. ACS Chem. Biol. 9, 2471-2478. doi: 10.1021/cb500515r
11. Bojang, P. Jr., and Ramos, K. S. (2014). The promise and failures of epigenetic therapies for cancer treatment. Cancer. Treat. Rev. 40, 153-169. doi: 10.1016/j.ctrv.2013.05.009
12. Cao, R., Wang, L. J., Wang, H. B., Xia, L., Erdjument-Bromage, H., Tempst, P., et al. (2002). Role of histone H3 lysine 27 methylation in polycomb-group silencing. Science 298, 1039-1043. doi: 10.1126/science.1076997
13. Centore, R. C., Havens, C. G., Manning, A. L., Li, J. M., Flynn, R. L., Tse, A., et al. (2010). CRL4(Cdt2)-mediated destruction of the histone methyltransferase Set8 prevents premature chromatin compaction in S phase. Mol. Cell 40, 22-33. doi: 10.1016/j.molcel.2010.09.015
14. Chang, Y., Ganesh, T., Horton, J. R., Spannhoff, A., Liu, J., Sun, A., et al. (2010). Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases. J. Mol. Biol. 400, 1-7. doi: 10.1016/j.jmb.2010.04.048
15. Chang, Y., Zhang, X., Horton, J. R., Upadhyay, A. K., Spannhoff, A., Liu, J., et al. (2009). Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nat. Struct. Mol. Biol. 16, 312-317. doi: 10.1038/nsmb.1560
16. Chen, M.-W., Hua, K.-T., Kao, H.-J., Chi, C.-C., Wei, L.-H., Johansson, G., et al. (2010). H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 70, 7830-7840. doi: 10.1158/0008-5472.CAN-10-0833
17. Cherblanc, F. L., Chapman, K. L., Brown, R., and Fuchter, M. J. (2013a). Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nat. Chem. Biol. 9, 136-137. doi: 10.1038/nchembio.1187
18. Cherblanc, F. L., Chapman, K. L., Reid, J., Borg, A. J., Sundriyal, S., Alcazar-Fuoli, L., et al. (2013b). On the histone lysine methyltransferase activity of fungal metabolite chaetocin. J. Med. Chem. 56, 8616-8625. doi: 10.1021/jm401063r
19. Chi, P., Allis, C. D., and Wang, G. G. (2010). Covalent histone modifications-miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10, 457-469. doi: 10.1038/nrc2876
20. Congdon, L. M., Houston, S. I., Veerappan, C. S., Spektor, T. M., and Rice, J. C. (2010). PR-Set7-mediated monomethylation of histone H4 lysine 20 at specific genomic regions induces transcriptional repression. J. Cell. Biochem. 110, 609-619. doi: 10.1002/jcb.22570
21. Copeland, R. A., Solomon, M. E., and Richon, V. M. (2009). Protein methyltransferases as a target class for drug discovery. Nat. Rev. Drug Discov. 8, 724-732. doi: 10.1038/nrd2974
22. Czermin, B., Melfi, R., Mccabe, D., Seitz, V., Imhof, A., and Pirrotta, V. (2002). Drosophila enhancer of Zeste/ESC complexes have a histone H3 methyltransferase activity that marks chromosomal Polycomb sites. Cell 111, 185-196. doi: 10.1016/S0092-8674(02)00975-3
23. Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Basavapathruni, A., Jin, L., Boriack-Sjodin, P. A., et al. (2013). Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122, 1017-1025. doi: 10.1182/blood-2013-04-497644
24. Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Majer, C. R., Sneeringer, C. J., Song, J., et al. (2011). Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53-65. doi: 10.1016/j.ccr.2011.06.009
25. Dhanak, D., and Jackson, P. (2014). Development and classes of epigenetic drugs for cancer. Biochem. Biophys. Res. Commun. 455, 58-69. doi: 10.1016/j.bbrc.2014.07.006
26. Dulev, S., Tkach, J., Lin, S., and Batada, N. N. (2014). SET8 methyltransferase activity during the DNA double-strand break response is required for recruitment of 53BP1. EMBO Rep. 15, 1163-1174. doi: 10.15252/embr.201439434
27. Eguchi, H., Kawaguchi, H., Yoshinaga, S., Nishida, A., Nishiguchi, T., and Fujisaki, S. (1994). Halogenation using N-Halogenocompounds. II. Acid catalyzed bromination of aromatic compounds with 1, 3-Dibromo-5, 5-dimethylhydantoin. Bull. Chem. Soc. Jpn. 67, 1918-1921. doi: 10.1246/bcsj.67.1918
28. Fang, J., Feng, Q., Ketel, C. S., Wang, H. B., Cao, R., Xia, L., et al. (2002). Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr. Biol. 12, 1086-1099. doi: 10.1016/S0960-9822(02)00924-7
29. Feng, Q., Wang, H. B., Ng, H. H., Erdjument-Bromage, H., Tempst, P., Struhl, K., et al. (2002). Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr. Biol. 12, 1052-1058. doi: 10.1016/S0960-9822(02)00901-6
30. Frederiks, F., Tzouros, M., Oudgenoeg, G., Van Welsem, T., Fornerod, M., Krijgsveld, J., et al. (2008). Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states. Nat. Struct. Mol. Biol. 15, 550-557. doi: 10.1038/nsmb.1432
31. Fujishiro, S., Dodo, K., Iwasa, E., Teng, Y., Sohtome, Y., Hamashima, Y., et al. (2013). Epidithiodiketopiperazine as a pharmacophore for protein lysine methyltransferase G9a inhibitors: reducing cytotoxicity by structural simplification. Bioorg. Med. Chem. Lett. 23, 733-736. doi: 10.1016/j.bmcl.2012.11.087
32. Garapaty-Rao, S., Nasveschuk, C., Gagnon, A., Chan, E. Y., Sandy, P., Busby, J., et al. (2013). Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse Large B cell lymphoma cell growth. Chem. Biol. 20, 1329-1339. doi: 10.1016/j.chembiol.2013.09.013
33. Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E., and Imhof, A. (2005). Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nat. Chem. Biol. 1, 143-145. doi: 10.1038/nchembio721
34. Hamada, T., Nishida, A., and Yonemitsu, O. (1986). Selective removal of electron-accepting Para-toluenesulfonyl and naphthalenesulfonyl protecting groups for amino function via photoinduced donor-acceptor ion-pairs with electron-donating aromatics. J. Am. Chem. Soc. 108, 140-145. doi: 10.1021/ja00261a023
35. Hauser, D., Weber, H. P., and Sigg, H. P. (1970). Isolation and structure elucidation of chaetocin. Helv. Chim. Acta 53, 1061-1073. doi: 10.1002/hlca.19700530521
36. He, Y. L., Korboukh, I., Jin, J., and Huang, J. (2012). Targeting protein lysine methylation and demethylation in cancers. Acta Biochim. Biophys. Sin. 44, 70-79. doi: 10.1093/abbs/gmr109
37. Helin, K., and Dhanak, D. (2013). Chromatin proteins and modifications as drug targets. Nature 502, 480-488. doi: 10.1038/nature12751
38. Houston, S. I., McManus, K. J., Adams, M. M., Sims, J. K., Carpenter, P. B., Hendzel, M. J., et al. (2008). Catalytic function of the PR-Set7 histone H4 lysine 20 monomethyltransferase is essential for mitotic entry and genomic stability. J. Biol. Chem. 283, 19478-19488. doi: 10.1074/jbc.M710579200
39. Hu, W. P., Wang, J. J., Lin, F. L., Lin, Y. C., Lin, S. R., and Hsu, M. H. (2001). An efficient synthesis of pyrrolo [2, 1-c] [1, 4]benzodiazepine. Synthesis of the antibiotic DC-81. J. Org. Chem. 66, 2881-2883. doi: 10.1021/jo010043d
40. Itoh, Y., Suzuki, T., and Miyata, N. (2013). Small-molecular modulators of cancer-associated epigenetic mechanisms. Mol. Biosyst. 9, 873-896. doi: 10.1039/c3mb25410k
41. Iwasa, E., Hamashima, Y., Fujishiro, S., Hashizume, D., and Sodeoka, M. (2011a). Total syntheses of chaetocin and ent-chaetocin. Tetrahedron 67, 6587-6599. doi: 10.1016/j.tet.2011.05.081
42. Iwasa, E., Hamashima, Y., Fujishiro, S., Higuchi, E., Ito, A., Yoshida, M., et al. (2010). Total synthesis of (+)-Chaetocin and its analogues: their histone methyltransferase G9a inhibitory activity. J. Am. Chem. Soc. 132, 4078-4079. doi: 10.1021/ja101280p
43. Iwasa, E., Hamashima, Y., and Sodeoka, M. (2011b). Epipolythiodiketopiperazine alkaloids: total syntheses and biological activities. Isr. J. Chem. 51, 420-433. doi: 10.1002/ijch.201100012
44. Jenuwein, T., Laible, G., Dorn, R., and Reuter, G. (1998). SET domain proteins modulate chromatin domains in eu-and heterochromatin. Cell. Mol. Life Sci. 54, 80-93. doi: 10.1007/s000180050127
45. Jorgensen, S., Elvers, I., Trelle, M. B., Menzel, T., Eskildsen, M., Jensen, O. N., et al. (2007). The histone methyltransferase SET8 is required for S-phase progression. J. Cell. Biol. 179, 1337-1345. doi: 10.1083/jcb.200706150
46. Kim, J., Ashenhurst, J. A., and Movassaghi, M. (2009). Total synthesis of (+)-11, 11 '-Dideoxyverticillin A. Science 324, 238-241. doi: 10.1126/science.1170777
47. Kim, J., and Movassaghi, M. (2010). General approach to epipolythiodiketopiperazine alkaloids: total synthesis of (+)-chaetocins A and C and (+)-12, 12 '-dideoxychetracin A. J. Am. Chem. Soc. 132, 14376-14378. doi: 10.1021/ja106869s
48. Kita, Y., Sano, A., Yamaguchi, T., Oka, M., Gotanda, K., and Matsugi, M. (1997). Additions of malononitrile radicals to alkenes under mild conditions using 2, 2'-azobis-(2, 4-dimethyl-4-methoxyvaleronitrile) (V-70) as an initiator. Tetrahedron Lett. 38, 3549-3552. doi: 10.1016/S0040-4039(97)00700-4
49. Kleer, C. G., Cao, Q., Varambally, S., Shen, R. L., Ota, L., Tomlins, S. A., et al. (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, 11606-11611. doi: 10.1073/pnas.1933744100
50. Knapp, S., and Weinmann, H. (2013). Small-molecule modulators for epigenetics targets. ChemMedChem 8, 1885-1891. doi: 10.1002/cmdc.201300344
51. Knutson, S. K., Kawano, S., Minoshima, Y., Warholic, N. M., Huang, K.-C., Xiao, Y., et al. (2014). Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-hodgkin lymphoma. Mol. Cancer Ther. 13, 842-854. doi: 10.1158/1535-7163.MCT-13-0773
52. Knutson, S. K., Warholic, N. M., Wigle, T. J., Klaus, C. R., Allain, C. J., Raimondi, A., et al. (2013). Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl. Acad. Sci. U.S.A. 110, 7922-7927. doi: 10.1073/pnas.1303800110
53. Knutson, S. K., Wigle, T. J., Warholic, N. M., Sneeringer, C. J., Allain, C. J., Klaus, C. R., et al. (2012). A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890-896. doi: 10.1038/nchembio.1084
54. Konze, K. D., Ma, A., Li, F., Barsyte-Lovejoy, D., Parton, T., Macnevin, C. J., et al. (2013). An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem. Biol. 8, 1324-1334. doi: 10.1021/cb400133j
55. Konze, K. D., Pattenden, S. G., Liu, F., Barsyte-Lovejoy, D., Li, F. L., Simon, J. M., et al. (2014). A chemical tool for in vitro and in vivo precipitation of lysine methyltransferase G9a. ChemMedChem 9, 549-553. doi: 10.1002/cmdc.201300450
56. Kubicek, S., O'sullivan, R. J., August, E. M., Hickey, E. R., Zhan, Q., Teodoro, M. L., et al. (2007). Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25, 473-481. doi: 10.1016/j.molcel.2007.01.017
57. Kuzmichev, A., Nishioka, K., Erdjument-Bromage, H., Tempst, P., and Reinberg, D. (2002). Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of Zeste protein. Gene. Dev. 16, 2893-2905. doi: 10.1101/gad.1035902
58. Lacoste, N., Utley, R. T., Hunter, J. M., Poirier, G. G., and Cote, J. (2002). Disruptor of telomeric silencing-1 is a chromatin-specific histone H3 methyltransferase. J. Biol. Chem. 277, 30421-30424. doi: 10.1074/jbc.C200366200
59. Li, Z., Nie, F., Wang, S., and Li, L. (2011). Histone H4 Lys 20 monomethylation by histone methylase SET8 mediates Wnt target gene activation. Proc. Natl. Acad. Sci. U.S.A. 108, 3116-3123. doi: 10.1073/pnas.1009353108
60. Liu, F., Barsyte-Lovejoy, D., Allali-Hassani, A., He, Y., Herold, J. M., Chen, X., et al. (2011). Optimization of cellular activity of G9a inhibitors 7-Aminoalkoxy-quinazolines. J. Med. Chem. 54, 6139-6150. doi: 10.1021/jm200903z
61. Liu, F., Barsyte-Lovejoy, D., Li, F., Xiong, Y., Korboukh, V., Huang, X.-P., et al. (2013). Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J. Med. Chem. 56, 8931-8942. doi: 10.1021/jm401480r
62. Liu, F., Chen, X., Allali-Hassani, A., Quinn, A. M., Wasney, G. A., Dong, A., et al. (2009). Discovery of a 2, 4-Diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J. Med. Chem. 52, 7950-7953. doi: 10.1021/jm901543m
63. Liu, F., Chen, X., Allali-Hassani, A., Quinn, A. M., Wigle, T. J., Wasney, G. A., et al. (2010). Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2, 4-Diamino-7-aminoalkoxy-quinazolines. J. Med. Chem. 53, 5844-5857. doi: 10.1021/jm100478y
64. Ma, A., Yu, W., Li, F., Bleich, R. M., Herold, J. M., Butler, K. V., et al. (2014a). Discovery of a selective, substrate-competitive inhibitor of the lysine methyltransferase SETD8. J. Med. Chem. 57, 6822-6833. doi: 10.1021/jm500871s
65. Ma, A., Yu, W., Xiong, Y., Butler, K., Brown, P., and Jin, J. (2014b). Structure-activity relationship studies of SETD8 inhibitors. Medchemcomm 5, 1892-1898. doi: 10.1039/C4MD00317A
66. Margueron, R., and Reinberg, D. (2011). The Polycomb complex PRC2 and its mark in life. Nature 469, 343-349. doi: 10.1038/nature09784
67. Mccabe, M. T., Ott, H. M., Ganji, G., Korenchuk, S., Thompson, C., Van Aller, G. S., et al. (2012). EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108-112. doi: 10.1038/nature11606
68. Mccloskey, D. E., Bale, S., Secrist, J. A., Tiwari, A., Moss, T. H., Valiyaveettil, J., et al. (2009). New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine†. J. Med. Chem. 52, 1388-1407. doi: 10.1021/jm801126a
69. Milne, T. A., Briggs, S. D., Brock, H. W., Martin, M. E., Gibbs, D., Allis, C. D., et al. (2002). MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol. Cell 10, 1107-1117. doi: 10.1016/S1097-2765(02)00741-4
70. Min, J. R., Feng, Q., Li, Z. Z., Zhang, Y., and Xu, R. M. (2003). Structure of the catalytic domain of human DOT1L, a Non-SET domain nucleosomal histone methyltransferase. Cell 112, 711-723. doi: 10.1016/S0092-8674(03)00114-4
71. Moore, J. A., and Kornreich, L. D. (1963). A direct synthesis of 4-aminoquinolines. Tetrahedron Lett. 4, 1277-1281. doi: 10.1016/S0040-4039(01)90818-4
72. Movassaghi, M., and Schmidt, M. A. (2007). Concise total synthesis of (-)-calycanthine, (+)-chimonanthine, and (+)-folicanthine. Angew. Chem. Int. Ed. 46, 3725-3728. doi: 10.1002/anie.200700705
73. Movassaghi, M., Schmidt, M. A., and Ashenhurst, J. A. (2008). Concise Total Synthesis of (+)-WIN 64821 and (-)-ditryptophenaline. Angew. Chem. Int. Ed. 47, 1485-1487. doi: 10.1002/anie.200704960
74. Muller, J., Hart, C. M., Francis, N. J., Vargas, M. L., Sengupta, A., Wild, B., et al. (2002). Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell 111, 197-208. doi: 10.1016/S0092-8674(02)00976-5
75. Nasveschuk, C. G., Gagnon, A., Garapaty-Rao, S., Balasubramanian, S., Campbell, R., Lee, C., et al. (2014). Discovery and optimization of tetramethylpiperidinyl benzamides as inhibitors of EZH2. ACS Med. Chem. Lett. 5, 378-383. doi: 10.1021/ml400494b
76. Ng, H. H., Feng, Q., Wang, H., Erdjument-Bromage, H., Tempst, P., Zhang, Y., et al. (2002). Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association. Gene. Dev. 16, 1518-1527. doi: 10.1101/gad.1001502
77. Nguyen, A. T., and Zhang, Y. (2011). The diverse functions of Dot1 and H3K79 methylation. Gene. Dep. 25, 1345-1358. doi: 10.1101/gad.2057811
78. Nishioka, K., Rice, J. C., Sarma, K., Erdjument-Bromage, H., Werner, J., Wang, Y. M., et al. (2002). PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol. Cell 9, 1201-1213. doi: 10.1016/S1097-2765(02)00548-8
79. Oda, H., Okamoto, I., Murphy, N., Chu, J., Price, S. M., Shen, M. M., et al. (2009). Monomethylation of histone H4-lysine 20 is involved in chromosome structure and stability and is essential for mouse development. Mol. Cell. Biol. 29, 2278-2295. doi: 10.1128/MCB.01768-08
80. Okada, Y., Feng, Q., Lin, Y. H., Jiang, Q., Li, Y. Q., Coffield, V. M., et al. (2005). hDOT1L links histone methylation to leukemogenesis. Cell 121, 167-178. doi: 10.1016/j.cell.2005.02.020
81. Olhava, E. J., Chesworth, R., Kuntz, K. W., Richon, V. M., Pollock, R. M., and Daigle, S. R. (2012). Preparation of substituted purine and 7-deazapurine compounds as modulators of epigenetic enzymes. PCT Int. Appl. WO 2012075381.
82. Pachaiyappan, B., and Woster, P. M. (2014). Design of small molecule epigenetic modulators. Bioorg. Med. Chem. Lett. 24, 21-32. doi: 10.1016/j.bmcl.2013.11.001
83. Qi, W., Chan, H., Teng, L., Li, L., Chuai, S., Zhang, R., et al. (2012). Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc. Natl. Acad. Sci. U.S.A. 109, 21360-21365. doi: 10.1073/pnas.1210371110
84. Rea, S., Eisenhaber, F., O'carroll, N., Strahl, B. D., Sun, Z. W., Schmid, M., et al. (2000). Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593-599. doi: 10.1038/35020506
85. Seela, F., and Ming, X. (2007). 7-Functionalized 7-deazapurine ß-d and β-l-ribonucleosides related to tubercidin and 7-deazainosine: glycosylation of pyrrolo[2, 3-d]pyrimidines with 1-O-acetyl-2, 3, 5-tri-O-benzoyl-ß-d or ß-l-ribofuranose. Tetrahedron 63, 9850-9861. doi: 10.1016/j.tet.2007.06.107
86. Shi, X., Kachirskaia, L., Yamaguchi, H., West, L. E., Wen, H., Wang, E. W., et al. (2007). Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol. Cell 27, 636-646. doi: 10.1016/j.molcel.2007.07.012
87. Shinkai, Y., and Tachibana, M. (2011). H3K9 methyltransferase G9a and the related molecule GLP. Gene. Dep. 25, 781-788. doi: 10.1101/gad.2027411
88. Smits, R. A., De Esch, I. J. P., Zuiderveld, O. P., Broeker, J., Sansuk, K., Guaita, E., et al. (2008). Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach. J. Med. Chem. 51, 7855-7865. doi: 10.1021/jm800876b
89. Sodeoka, M., Dodo, K., Teng, Y. O., Iuchi, K., Hamashima, Y., Iwasa, E., et al. (2012). Synthesis and biological activities of chaetocin and its derivatives. Pure Appl. Chem. 84, 1369-1378. doi: 10.1351/PAC-CON-11-10-31
90. Spannhoff, A., Hauser, A. T., Heinke, R., Sippl, W., and Jung, M. (2009). The emerging therapeutic potential of histone methyltransferase and demethylase inhibitors. ChemMedChem 4, 1568-1582. doi: 10.1002/cmdc.200900301
91. Srimongkolpithak, N., Sundriyal, S., Li, F., Vedadi, M., and Fuchter, M. J. (2014). Identification of 2, 4-diamino-6, 7-dimethoxyquinoline derivatives as G9a inhibitors. Medchemcomm 5, 1821-1828. doi: 10.1039/C4MD00274A
92. Strahl, B. D., Grant, P. A., Briggs, S. D., Sun, Z. W., Bone, J. R., Caldwell, J. A., et al. (2002). Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol. Cell. Biol. 22, 1298-1306. doi: 10.1128/MCB.22.5.1298-1306.2002
93. Sweis, R. F., Pliushchev, M., Brown, P. J., Guo, J., Li, F. L., Maag, D., et al. (2014). Discovery and development of potent and selective inhibitors of histone methyltransferase G9a. ACS Med. Chem. Lett. 5, 205-209. doi: 10.1021/ml400496h
94. Tachibana, M., Sugimoto, K., Nozaki, M., Ueda, J., Ohta, T., Ohki, M., et al. (2002). G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Gene. Dep. 16, 1779-1791. doi: 10.1101/gad.989402
95. Tachibana, M., Ueda, J., Fukuda, M., Takeda, N., Ohta, T., Iwanari, H., et al. (2005). Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Gene. Dep. 19, 815-826. doi: 10.1101/gad.1284005
96. Takawa, M., Cho, H.-S., Hayami, S., Toyokawa, G., Kogure, M., Yamane, Y., et al. (2012). Histone lysine methyltransferase SETD8 promotes carcinogenesis by deregulating PCNA expression. Cancer Res. 72, 3217-3227. doi: 10.1158/0008-5472.CAN-11-3701
97. Thurston, D. E., Murty, V. S., Langley, D. R., and Jones, G. B. (1990). O-Debenzylation of a pyrrolo[2, 1-c][1, 4]benzodiazepine in the presence of a carbinolamine functionality: synthesis of DC-81. Synthesis 1, 81-84. doi: 10.1055/s-1990-26795
98. Tian, X., Zhang, S., Liu, H. M., Zhang, Y. B., Blair, C. A., Mercola, D., et al. (2013). Histone lysine-specific methyltransferases and demethylases in carcinogenesis: new targets for cancer therapy and prevention. Curr. Cancer Drug Targets 13, 558-579. doi: 10.2174/1568009611313050007
99. Van Leeuwen, F., Gafken, P. R., and Gottschling, D. E. (2002). Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell 109, 745-756. doi: 10.1016/S0092-8674(02)00759-6
100. Varambally, S., Dhanasekaran, S. M., Zhou, M., Barrette, T. R., Kumar-Sinha, C., Sanda, M. G., et al. (2002). The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624-629. doi: 10.1038/nature01075
101. Vedadi, M., Barsyte-Lovejoy, D., Liu, F., Rival-Gervier, S., Allali-Hassani, A., Labrie, V., et al. (2011). A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat. Chem. Biol. 7, 566-574. doi: 10.1038/nchembio.599
102. Verma, S. K., Tian, X., Lafrance, L. V., Duquenne, C., Suarez, D. P., Newlander, K. A., et al. (2012). Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med. Chem. Lett. 3, 1091-1096. doi: 10.1021/ml3003346
103. Wagner, T., Robaa, D., Sippl, W., and Jung, M. (2014). Mind the methyl: methyllysine binding proteins in epigenetic regulation. ChemMedChem 9, 466-483. doi: 10.1002/cmdc.201300422
104. Wang, H. B., Cao, R., Xia, L., Erdjument-Bromage, H., Borchers, C., Tempst, P., et al. (2001). Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol. Cell 8, 1207-1217. doi: 10.1016/S1097-2765(01)00405-1
105. Wang, Z., and Patel, D. J. (2013). Small molecule epigenetic inhibitors targeted to histone lysine methyltransferases and demethylases. Q. Rev. Biophys. 46, 349-373. doi: 10.1017/S0033583513000085
106. Williams, D. E., Dalisay, D. S., Li, F. L., Amphlett, J., Maneerat, W., Chavez, M., et al. (2013). Nahuoic acid a produced by a streptomyces sp isolated from a marine sediment is a selective SAM-competitive inhibitor of the histone methyltransferase SETD8. Org. Lett. 5, 414-417. doi: 10.1021/ol303416k
107. Wu, S., Wang, W., Kong, X., Congdon, L. M., Yokomori, K., Kirschner, M. W., et al. (2010). Dynamic regulation of the PR-Set7 histone methyltransferase is required for normal cell cycle progression. Gene. Dev. 24, 2531-2542. doi: 10.1101/gad.1984210
108. Yang, F., Sun, L., Li, Q., Han, X., Lei, L., Zhang, H., et al. (2012). SET8 promotes epithelial-mesenchymal transition and confers TWIST dual transcriptional activities. EMBO J. 31, 110-123. doi: 10.1038/emboj.2011.364
109. Yao, Y., Chen, P. H., Diao, J. S., Cheng, G., Deng, L. S., Anglin, J. L., et al. (2012). Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. J. Am. Chem. Soc. 134, 17834-17834. doi: 10.1021/ja309785w
110. Yao, Y., Chen, P., Diao, J., Cheng, G., Deng, L., Anglin, J. L., et al. (2011). Selective inhibitors of histone methyltransferase dot1l: design, synthesis, and crystallographic studies. J. Am. Chem. Soc. 133, 16746-16749. doi: 10.1021/ja206312b
111. Yu, W., Chory, E. J., Wernimont, A. K., Tempel, W., Scopton, A., Federation, A., et al. (2012). Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat. Commun. 3:1288. doi: 10.1038/ncomms2304
112. Yu, W., Chory, E. J., Wernimont, A. K., Tempel, W., Scopton, A., Federation, A., et al. (2013a). Corrigendum: catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors (vol 3, 1288, 2012). Nat. Commun. 4:1893. doi: 10.1038/Ncomms2845
113. Yu, W., Smil, D., Li, F. L., Tempel, W., Fedorov, O., Nguyen, K. T., et al. (2013b). Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorg. Med. Chem. 21, 1787-1794. doi: 10.1016/j.bmc.2013.01.049
114. Yuan, Y., Wang, Q., Paulk, J., Kubicek, S., Kemp, M. M., Adams, D. J., et al. (2012). A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem. Biol. 7, 1152-1157. doi: 10.1021/cb300139y
115. Zhu, J. (1997). SNAr bases macrocyclization via biaryl ether formation: application in natural product synthesis. Synlett 2, 133-144. doi: 10.1055/s-1997-722