A chemical probe toolbox for dissecting the cancer epigenome

Nature Reviews Cancer

Volumn 17, Issue 3, 2017, Pages 160-183

  Shortt, Jake ^a,b,c   Ott, Christopher J ^d,e,f   Johnstone, Ricky W ^a,b   Bradner, James E ^d,e,f  

^a PETER MACCALLUM CANCER CENTRE   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c MONASH UNIVERSITY   (Australia)

^d DANA FARBER CANCER INSTITUTE   (United States)

^e HARVARD MEDICAL SCHOOL   (United States)

^f BROAD INSTITUTE OF MIT AND HARVARD   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLLYSINE RECOGNITION DOMAIN INHIBITOR; DNA; DNA METHYLTRANSFERASE INHIBITOR; FLAVINE ADENINE NUCLEOTIDE; HISTONE ACETYLTRANSFERASE INHIBITOR; HISTONE DEMETHYLASE; HISTONE DEMETHYLASE INHIBITOR; HISTONE METHYLTRANSFERASE INHIBITOR; METHYLLYSINE RECOGNITION DOMAIN INHIBITOR; METHYLTRANSFERASE INHIBITOR; UNCLASSIFIED DRUG; EZH2 PROTEIN, HUMAN; HISTONE ACETYLTRANSFERASE; HISTONE LYSINE METHYLTRANSFERASE; HISTONE METHYLTRANSFERASE; SIRTUIN; TRANSCRIPTION FACTOR EZH2;

CANCER CELL; CANCER GENETICS; CANCER THERAPY; CARCINOGENESIS; CHEMICAL STRUCTURE; DNA BINDING; DNA METHYLATION; DNA MODIFICATION; EPIGENETICS; EUCHROMATIN; HETEROCHROMATIN; HISTONE ACETYLATION; HISTONE METHYLATION; HUMAN; NUCLEOSOME; PHYLOGENY; PRIORITY JOURNAL; REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; GENETICS; NEOPLASMS;

ANIMALS; DNA METHYLATION; ENHANCER OF ZESTE HOMOLOG 2 PROTEIN; EPIGENOMICS; HISTONE ACETYLTRANSFERASES; HISTONE DEMETHYLASES; HISTONE-LYSINE N-METHYLTRANSFERASE; HUMANS; NEOPLASMS; SIRTUINS;

EID: 85013638949     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc.2016.148     Document Type: Review

References (302)

1. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693-705 (2007).
2. Ho, L., & Crabtree, G. R. Chromatin remodelling during development. Nature 463, 474-484 (2010).
3. Patel, M. N., Halling-Brown, M. D., Tym, J. E., Workman, P., & Al Lazikani, B. Objective assessment of cancer genes for drug discovery. Nat. Rev. Drug Discov. 12, 35-50 (2013).
4. Futreal, P. A., et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177-183 (2004).
5. Patel, J. P., et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 366, 1079-1089 (2012).
6. Shih, A. H., Abdel-Wahab, O., Patel, J. P., & Levine, R. L. The role of mutations in epigenetic regulators in myeloid malignancies. Nat. Rev. Cancer 12, 599-612 (2012).
7. Shi, J., et al. Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev. 27, 2648-2662 (2013).
8. Yan, H., et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765-773 (2009).
9. Simon, J. A., & Lange, C. A. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res. 647, 21-29 (2008).
10. Morin, R. D., et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B cell lymphomas of germinal-center origin. Nat. Genet. 42, 181-185 (2010).
11. van Haaften, G., et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521-523 (2009).
12. Wilson, B. G., & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11, 481-492 (2011).
13. Kadoch, C., et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat. Genet. 45, 592-601 (2013).
14. Versteege, I., et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203-206 (1998).
15. Jones, S., et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228-231 (2010).
16. Wiegand, K. C., et al. ARID1A mutations in endometriosis-Associated ovarian carcinomas. N. Engl. J. Med. 363, 1532-1543 (2010).
17. Dawson, M. A., & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12-27 (2012).
18. Shen, H., & Laird, P. W. Interplay between the cancer genome and epigenome. Cell 153, 38-55 (2013).
19. Berg, T. Inhibition of transcription factors with small organic molecules. Curr. Opin. Chem. Biol. 12, 464-471 (2008).
20. Darnell, J. E. Jr. Transcription factors as targets for cancer therapy. Nat. Rev. Cancer 2, 740-749 (2002).
21. Koehler, A. N. A complex task? Direct modulation of transcription factors with small molecules. Curr. Opin. Chem. Biol. 14, 331-340 (2010).
22. Winter, G. E., et al. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376-1381 (2015).
23. Frye, S. V. The art of the chemical probe. Nat. Chem. Biol. 6, 159-161 (2010).
24. Tanaka, M., Roberts, J. M., Qi, J., & Bradner, J. E. Inhibitors of emerging epigenetic targets for cancer therapy: a patent review (2010-2014). Pharm. Pat. Anal. 4, 261-284 (2015).
25. Copeland, R. A., Solomon, M. E., & Richon, V. M. Protein methyltransferases as a target class for drug discovery. Nat. Rev. Drug Discov. 8, 724-732 (2009).
26. Smith, B. C., & Denu, J. M. Chemical mechanisms of histone lysine and arginine modifications. Biochim. Biophys. Acta 1789, 45-57 (2009).
27. Luo, M. Current chemical biology approaches to interrogate protein methyltransferases. ACS Chem. Biol. 7, 443-463 (2012).
28. Okada, Y., et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167-178 (2005).
29. Vedel, M., Lawrence, F., Robert-Gero, M., & Lederer, E. The antifungal antibiotic sinefungin as a very active inhibitor of methyltransferases and of the transformation of chick embryo fibroblasts by Rous sarcoma virus. Biochem. Biophys. Res. Commun. 85, 371-376 (1978).
30. Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E., & Imhof, A. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3 9. Nat. Chem. Biol. 1, 143-145 (2005).
31. Cherblanc, F. L., Chapman, K. L., Brown, R., & Fuchter, M. J. Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nat. Chem. Biol. 9, 136-137 (2013).
32. Bartel, R. L., & Borchardt, R. T. Effects of adenosine dialdehyde on S adenosylhomocysteine hydrolase and S adenosylmethionine-dependent transmethylations in mouse L929 cells. Mol. Pharmacol. 25, 418-424 (1984).
33. Jarvi, E. T., et al. 4, 5. unsaturated 5. halogenated nucleosides. Mechanism-based and competitive inhibitors of S adenosyl-l homocysteine hydrolase. J. Med. Chem. 34, 647-656 (1991).
34. Clarke, S. G. in The Enzymes: Protein Methyltransferases Vol. 24 (eds Clarke, S. G., & Tamanoi, F.) 467-493 (Elsevier, 2006).
35. Miranda, T. B., et al. DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Mol. Cancer Ther. 8, 1579-1588 (2009).
36. Paller, A. S., Arnsmeier, S. L., Clark, S. H., & Mirkin, B. L. Z-4?, 5? didehydro 5? deoxy 5? fluoroadenosine (MDL 28, 842), an irreversible inhibitor of S adenosylhomocysteine hydrolase, suppresses proliferation of cultured keratinocytes and squamous carcinoma cell lines. Cancer Res. 53, 6058-6060 (1993).
37. Tan, J., et al. Pharmacologic disruption of Polycomb-repressive complex 2 mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 21, 1050-1063 (2007).
38. Tachibana, M., et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779-1791 (2002).
39. McGarvey, K. M., et al. Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state. Cancer Res. 66, 3541-3549 (2006).
40. Kondo, Y., et al. Downregulation of histone H3 lysine 9 methyltransferase G9a induces centrosome disruption and chromosome instability in cancer cells. PLoS ONE 3, e2037 (2008).
41. Ding, J., et al. The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metab. 18, 896-907 (2013).
42. Kubicek, S., et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25, 473-481 (2007).
43. Chang, Y., et al. Structural basis for G9a like protein lysine methyltransferase inhibition by BIX 01294. Nat. Struct. Mol. Biol. 16, 312-317 (2009).
44. Liu, F., et al. 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 (2009).
45. Liu, F., et al. Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2, 4 diamino 7 aminoalkoxy-quinazolines. J. Med. Chem. 53, 5844-5857 (2010).
46. Liu, F., et al. Optimization of cellular activity of G9a inhibitors 7 aminoalkoxy-quinazolines. J. Med. Chem. 54, 6139-6150 (2011).
47. Vedadi, M., et al. A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nat. Chem. Biol. 7, 566-574 (2011).
48. Liu, F., et al. Discovery of an in vivo chemical probe of the lysine methyltransferases G9a and GLP. J. Med. Chem. 56, 8931-8942 (2013).
49. Lehnertz, B., et al. The methyltransferase G9a regulates HoxA9 dependent transcription in AML. Genes Dev. 28, 317-327 (2014).
50. Chen, X., et al. G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. Genes Dev. 26, 2499-2511 (2012).
51. Sweis, R. F., et al. Discovery and development of potent and selective inhibitors of histone methyltransferase G9a. ACS Med. Chem. Lett. 5, 205-209 (2014).
52. Pappano, W. N., et al. The histone methyltransferase inhibitor A-366 uncovers a role for G9a/GLP in the epigenetics of leukemia. PLoS ONE 10, e0131716 (2015).
53. Yuan, Y., et al. A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem. Biol. 7, 1152-1157 (2012).
54. Bernt, K. M., et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66-78 (2011).
55. Rau, R. E., et al. DOT1L as a therapeutic target for the treatment of DNMT3A mutant acute myeloid leukemia. Blood 128, 971-981 (2016).
56. Min, J., Feng, Q., Li, Z., Zhang, Y., & Xu, R. M. Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell 112, 711-723 (2003).
57. Richon, V. M., et al. Chemogenetic analysis of human protein methyltransferases. Chem. Biol. Drug Des. 78, 199-210 (2011).
58. Daigle, S. R., et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53-65 (2011).
59. Yu, W., et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat. Commun. 3, 1288 (2012).
60. Basavapathruni, A., et al. Conformational adaptation drives potent, selective and durable inhibition of the human protein methyltransferase DOT1L. Chem. Biol. Drug Des. 80, 971-980 (2012).
61. Daigle, S. R., et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122, 1017-1025 (2013).
62. Yao, Y., et al. Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. J. Am. Chem. Soc. 133, 16746-16749 (2011).
63. Yu, W., et al. Bromo-deaza-SAH: a potent and selective DOT1L inhibitor. Bioorg. Med. Chem. 21, 1787-1794 (2013).
64. Deng, L., et al. Synthesis, activity and metabolic stability of non-ribose containing inhibitors of histone methyltransferase DOT1L. MedChemComm. 4, 822-826 (2013).
65. Yi, J. S., et al. Structure-guided DOT1L probe optimization by label-free ligand displacement. ACS Chem. Biol. 10, 667-674 (2015).
66. Karatas, H., et al. High-Affinity, small-molecule peptidomimetic inhibitors of MLL1/WDR5 protein-protein interaction. J. Am. Chem. Soc.135, 669-682 (2013).
67. Cao, F., et al. Targeting MLL1 H3K4 methyltransferase activity in mixed-lineage leukemia. Mol. Cell 53, 247-261 (2014).
68. Grembecka, J., et al. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol. 8, 277-284 (2012).
69. He, S., et al. High-Affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction. J. Med. Chem. 57, 1543-1556 (2014).
70. McCabe, M. T., et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2 activating mutations. Nature 492, 108-112 (2012).
71. Knutson, S. K., et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890-896 (2012).
72. Qi, W., et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc. Natl Acad. Sci. USA 109, 21360-21365 (2012).
73. Riising, E. M., et al. Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide. Mol. Cell 55, 347-360 (2014).
74. Margueron, R., et al. Ezh1 and Ezh2 maintain repressive chromatin through different mechanisms. Mol. Cell 32, 503-518 (2008).
75. Varambally, S., et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624-629 (2002).
76. Kleer, C. G., et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606-11611 (2003).
77. Morin, R. D., et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298-303 (2011).
78. Velichutina, I., et al. EZH2 mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116, 5247-5255 (2010).
79. Béguelin, W., et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677-692 (2013).
80. LaFave, L. M., et al. Loss of BAP1 function leads to EZH2 dependent transformation. Nat. Med. 21, 1344-1349 (2015).
81. Garapaty-Rao, S., et al. Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth. Chem. Biol. 20, 1329-1339 (2013).
82. Nasveschuk, C. G., et al. Discovery and optimization of tetramethylpiperidinyl benzamides as inhibitors of EZH2. ACS Med. Chem. Lett. 5, 378-383 (2014).
83. Konze, K. D., et al. An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem. Biol. 8, 1324-1334 (2013).
84. Knutson, S. K., et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl Acad. Sci. USA 110, 7922-7927 (2013).
85. Verma, S. K., et al. Identification of potent, selective, cell-Active inhibitors of the histone lysine methyltransferase EZH2. ACS Med. Chem. Lett. 3, 1091-1096 (2012).
86. Knutson, S. K., et al. Selective inhibition of EZH2 by EPZ 6438 leads to potent antitumor activity in EZH2 mutant non-Hodgkin lymphoma. Mol. Cancer Ther. 13, 842-854 (2014).
87. Alimova, I., et al. Inhibition of EZH2 suppresses self-renewal and induces radiation sensitivity in atypical rhabdoid teratoid tumor cells. Neuro Oncol. 15, 149-160 (2013).
88. Shi, J., et al. The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL AF9;Nras(G12D) acute myeloid leukemia. Oncogene 32, 930-938 (2013).
89. Neff, T., et al. Polycomb repressive complex 2 is required for MLL AF9 leukemia. Proc. Natl Acad. Sci. USA 109, 5028-5033 (2012).
90. Xu, B., Konze, K. D., Jin, J., & Wang, G. G. Targeting EZH2 and PRC2 dependence as novel anticancer therapy. Exp. Hematol. 43, 698-712 (2015).
91. Jiao, L., & Liu, X. Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2. Science 350, aac4383 (2015).
92. McBride, A. E., & Silver, P. A. State of the arg: protein methylation at arginine comes of age. Cell 106, 5-8 (2001).
93. Yang, Y., & Bedford, M. T. Protein arginine methyltransferases and cancer. Nat. Rev. Cancer 13, 37-50 (2013).
94. Tarighat, S. S., et al. The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation. Leukemia 30, 789-799 (2016).
95. Chung, J., et al. Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing. J. Biol. Chem. 288, 35534-35547 (2013).
96. Kryukov, G. V., et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214-1218 (2016).
97. Alinari, L., et al. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B cell transformation. Blood 125, 2530-2543 (2015).
98. Chan-Penebre, E., et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat. Chem. Biol. 11, 432-437 (2015).
99. Mitchell, L. H., et al. Aryl pyrazoles as potent inhibitors of arginine methyltransferases: identification of the first PRMT6 tool compound. ACS Med. Chem. Lett. 6, 655-659 (2015).
100. Kaniskan, H. U., et al. A potent, selective and cell-Active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3). Angew. Chem. Int. Ed. 54, 5166-5170 (2015).
101. Eram, M. S., et al. A potent, selective, and cell-Active inhibitor of human type I protein arginine methyltransferases. ACS Chem. Biol. 11, 772-781 (2016).
102. Shi, Y., et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941-953 (2004).
103. Metzger, E., et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436-439 (2005).
104. Amente, S., Lania, L., & Majello, B. The histone LSD1 demethylase in stemness and cancer transcription programs. Biochim. Biophys. Acta 1829, 981-986 (2013).
105. Yang, Z. Q., et al. Identification of a novel gene, GASC1, within an amplicon at 9p23 24 frequently detected in esophageal cancer cell lines. Cancer Res. 60, 4735-4739 (2000).
106. Hu, Z., et al. A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31. Oncogene 20, 6946-6954 (2001).
107. Yamane, K., et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483-495 (2006).
108. Wissmann, M., et al. Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expression. Nat. Cell Biol. 9, 347-353 (2007).
109. Lee, M. G., Wynder, C., Schmidt, D. M., McCafferty, D. G., & Shiekhattar, R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem. Biol. 13, 563-567 (2006).
110. Schmidt, D. M., & McCafferty, D. G. trans 2 phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46, 4408-4416 (2007).
111. Yang, M., et al. Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans 2 phenylcyclopropylamine. Biochemistry 46, 8058-8065 (2007).
112. Ueda, R., et al. Identification of cell-Active lysine specific demethylase 1 selective inhibitors. J. Am. Chem. Soc.131, 17536-17537 (2009).
113. Binda, C., et al. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J. Am. Chem. Soc. 132, 6827-6833 (2010).
114. Mimasu, S., et al. Structurally designed trans 2 phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1. Biochemistry 49, 6494-6503 (2010).
115. Harris, W. J., et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL AF9 leukemia stem cells. Cancer Cell 21, 473-487 (2012).
116. Liang, Y., et al. A novel selective LSD1/KDM1A inhibitor epigenetically blocks herpes simplex virus lytic replication and reactivation from latency. mBio 4, e00558 12 (2013).
117. Mohammad, H. P., et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell 28, 57-69 (2015).
118. Schenk, T., et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-Trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605-611 (2012).
119. Mould, D. P., McGonagle, A. E., Wiseman, D. H., Williams, E. L., & Jordan, A. M. Reversible inhibitors of LSD1 as therapeutic agents in acute myeloid leukemia: clinical significance and progress to date. Med. Res. Rev. 35, 586-618 (2015).
120. Mohammad, H., et al. Novel anti-Tumor activity of targeted LSD1 inhibition by GSK2879552. Eur. J. Cancer 50, 72 (2014).
121. Smith, E. H., Janknecht, R., & Maher, L. J. III. Succinate inhibition of alpha-ketoglutarate-dependent enzymes in a yeast model of paraganglioma. Hum. Mol. Genet. 16, 3136-3148 (2007).
122. Rose, N. R., et al. Inhibitor scaffolds for 2 oxoglutarate-dependent histone lysine demethylases. J. Med. Chem. 51, 7053-7056 (2008).
123. Rose, N. R., et al. Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. J. Med. Chem. 53, 1810-1818 (2010).
124. Sekirnik, R., et al. Inhibition of the histone lysine demethylase JMJD2A by ejection of structural Zn(II). Chem. Commun. (Camb.) 42, 6376-6378 (2009).
125. Culhane, J. C., et al. A mechanism-based inactivator for histone demethylase LSD1. J. Am. Chem. Soc. 128, 4536-4537 (2006).
126. Hamada, S., et al. Synthesis and activity of N oxalylglycine and its derivatives as Jumonji C domain-containing histone lysine demethylase inhibitors. Bioorg. Med. Chem. Lett. 19, 2852-2855 (2009).
127. King, O. N., et al. Quantitative high-Throughput screening identifies 8 hydroxyquinolines as cell-Active histone demethylase inhibitors. PLoS ONE 5, e15535 (2010).
128. Thalhammer, A., et al. Inhibition of the histone demethylase JMJD2E by 3 substituted pyridine 2, 4 dicarboxylates. Org. Biomol. Chem. 9, 127-135 (2011).
129. Luo, X., et al. A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases. J. Am. Chem. Soc.133, 9451-9456 (2011).
130. Kruidenier, L., et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404-408 (2012).
131. Ntziachristos, P., et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514, 513-517 (2014).
132. Hashizume, R., et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394-1396 (2014).
133. Heinemann, B., et al. Inhibition of demethylases by GSK J1/J4. Nature 514, E1-E2 (2014).
134. Taverna, S. D., Li, H., Ruthenburg, A. J., Allis, C. D., & Patel, D. J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 14, 1025-1040 (2007).
135. Wang, G. G., et al. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger. Nature 459, 847-851 (2009).
136. James, L. I., et al. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nat. Chem. Biol. 9, 184-191 (2013).
137. James, L. I., et al. Small-molecule ligands of methyl-lysine binding proteins: optimization of selectivity for L3MBTL3. J. Med. Chem. 56, 7358-7371 (2013).
138. Milosevich, N., et al. Selective inhibition of CBX6: a methyllysine reader protein in the Polycomb family. ACS Med. Chem. Lett. 7, 139-144 (2016).
139. Stuckey, J. I., et al. A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1. Nat. Chem. Biol. 12, 180-187 (2016).
140. Choudhary, C., et al. Lysine acetylation targets protein complexes and co regulates major cellular functions. Science 325, 834-840 (2009).
141. Roth, S. Y., Denu, J. M., & Allis, C. D. Histone acetyltransferases. Annu. Rev. Biochem. 70, 81-120 (2001).
142. Sun, X. J., Man, N., Tan, Y., Nimer, S. D., & Wang, L. The role of histone acetyltransferases in normal and malignant hematopoiesis. Front. Oncol. 5, 108 (2015).
143. Bowers, E. M., et al. Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem. Biol. 17, 471-482 (2010).
144. Ogiwara, H., et al. Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality via apoptotic cell death due to abrogation of MYC expression. Cancer Discov. 6, 430-445 (2015).
145. Wang, L., et al. The leukemogenicity of AML1 ETO is dependent on site-specific lysine acetylation. Science 333, 765-769 (2011).
146. Arif, M., et al. Nitric oxide-mediated histone hyperacetylation in oral cancer: target for a water-soluble HAT inhibitor, CTK7A. Chem. Biol. 17, 903-913 (2010).
147. Yang, H., et al. Small-molecule inhibitors of acetyltransferase p300 identified by high-Throughput screening are potent anticancer agents. Mol. Cancer Ther. 12, 610-620 (2013).
148. Ravindra, K. C., et al. Inhibition of lysine acetyltransferase KAT3B/p300 activity by a naturally occurring hydroxynaphthoquinone, plumbagin. J. Biol. Chem. 284, 24453-24464 (2009).
149. Modak, R., et al. Probing p300/CBP associated factor (PCAF)-dependent pathways with a small molecule inhibitor. ACS Chem. Biol. 8, 1311-1323 (2013).
150. Shirakawa, K., et al. Salicylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. eLife 5, e11156 (2016).
151. Liu, X., et al. The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451, 846-850 (2008).
152. Delvecchio, M., Gaucher, J., Aguilar-Gurrieri, C., Ortega, E., & Panne, D. Structure of the p300 catalytic core and implications for chromatin targeting and HAT regulation. Nat. Struct. Mol. Biol. 20, 1040-1046 (2013).
153. Bolden, J. E., Peart, M. J., & Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5, 769-784 (2006).
154. Sternson, S. M., Wong, J. C., Grozinger, C. M., & Schreiber, S. L. Synthesis of 7200 small molecules based on a substructural analysis of the histone deacetylase inhibitors trichostatin and trapoxin. Org. Lett. 3, 4239-4242 (2001).
155. Gregoretti, I. V., Lee, Y. M., & Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338, 17-31 (2004).
156. Bradner, J. E., et al. Chemical phylogenetics of histone deacetylases. Nat. Chem. Biol. 6, 238-243 (2010).
157. Bantscheff, M., et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol. 29, 255-265 (2011).
158. Wong, J. C., Hong, R., & Schreiber, S. L. Structural biasing elements for in cell histone deacetylase paralog selectivity. J. Am. Chem. Soc. 125, 5586-5587 (2003).
159. Kwon, H. J., Owa, T., Hassig, C. A., Shimada, J., & Schreiber, S. L. Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. Proc. Natl Acad. Sci. USA 95, 3356-3361 (1998).
160. Hassig, C. A., et al. KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo. Mol. Cancer Ther. 7, 1054-1065 (2008).
161. Huang, H. L., et al. Anticancer activity of MPT0E028, a novel potent histone deacetylase inhibitor, in human colorectal cancer HCT116 cells in vitro and in vivo. PLoS ONE 7, e43645 (2012).
162. Tsuji, N., Kobayashi, M., Nagashima, K., Wakisaka, Y., & Koizumi, K. A new antifungal antibiotic, trichostatin. J. Antibiot. 29, 1-6 (1976).
163. Sugita, K., Koizumi, K., & Yoshida, H Morphological Reversion of Sis-Transformed NIH3T3 Cells by Trichostatin A. Cancer Res. 52, 168-172 (1992).
164. Avila, A. M., et al. Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy. J. Clin. Invest. 117, 659-671 (2007).
165. Olsen, E. A., et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T cell lymphoma. J. Clin. Oncol. 25, 3109-3115 (2007).
166. Matthews, G. M., et al. Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies. Blood 126, 2392-2403 (2015).
167. Minami, J., et al. Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia 28, 680-689 (2014).
168. Wells, C. E., et al. Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS ONE 8, e68915 (2013).
169. Göttlicher, M., et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 20, 6969-6978 (2001).
170. Riggs, M. G., Whittaker, R. G., Neumann, J. R., & Ingram, V. M. n Butyrate causes histone modification in HeLa and Friend erythroleukaemia cells. Nature 268, 462-464 (1977).
171. Candelaria, M., et al. Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase II trial. Ann. Hematol. 90, 379-387 (2011).
172. Coiffier, B., et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T cell lymphoma after prior systemic therapy. J. Clin. Oncol. 30, 631-636 (2012).
173. Furumai, R., et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res. 62, 4916-4921 (2002).
174. Whittaker, S. J., et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T cell lymphoma. J. Clin. Oncol. 28, 4485-4491 (2010).
175. El Beltagi, H. M., Martens, A. C. M., Lelieveld, P., Haroun, E. A., & Hagenbeek, A. 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, 3008-3014 (1993).
176. Saito, A., et al. A synthetic inhibitor of histone deacetylase, MS 27 275, with marked in vivo antitumor activity against human tumors Proc. Natl Acad. Sci. USA 96, 4592-4597 (1999).
177. Paquin, I., et al. Design and synthesis of 4-[(s triazin 2 ylamino)methyl]-N-(2 aminophenyl)-benzamides and their analogues as a novel class of histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 18, 1067-1071 (2008).
178. Chou, C. J., Herman, D., & Gottesfeld, J. M. Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. J. Biol. Chem. 283, 35402-35409 (2008).
179. Methot, J. L., et al. Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/ HDAC2 inhibitors (SHI 1:2). Bioorg. Med. Chem. Lett. 18, 973-978 (2008).
180. Jayathilaka, N., et al. Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2. Nucleic Acids Res. 40, 5378-5388 (2012).
181. Ontoria, J. M., et al. Identification of novel, selective, and stable inhibitors of class II histone deacetylases. Validation studies of the enzymatic activity of HDAC4 by small molecules as a novel approach for cancer therapy. J. Med. Chem. 52, 6782-6783 (2009).
182. Lobera, M., et al. Selective class IIa histone deacetylase inhibition via a non-chelating zinc-binding group. Nat. Chem. Biol. 9, 319-325 (2013).
183. Mai, A., et al. Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxamides. J. Med. Chem. 48, 3344-3353 (2005).
184. Chalkiadaki, A., & Guarente, L. The multifaceted functions of sirtuins in cancer. Nat. Rev. Cancer 15, 608-624 (2015).
185. Wang, R. H., et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 14, 312-323 (2008).
186. Roth, M., & Chen, W. Y. Sorting out functions of sirtuins in cancer. Oncogene 33, 1609-1620 (2014).
187. Villalba, J. M., & Alcain, F. J. Sirtuin activators and inhibitors. BioFactors 38, 349-359 (2012).
188. Howitz, K. T., et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191-196 (2003).
189. Milne, J. C., et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712-716 (2007).
190. Chauhan, D., et al. Preclinical evaluation of a novel SIRT1 modulator SRT1720 in multiple myeloma cells. Br. J. Haematol. 155, 588-598 (2011).
191. Chen, C. W., et al. DOT1L inhibits SIRT1 mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia. Nat. Med. 21, 335-343 (2015).
192. Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M., & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099-45107 (2002).
193. Smith, B. C., & Denu, J. M. Mechanism-based inhibition of Sir2 deacetylases by thioacetyl-lysine peptide. Biochemistry 46, 14478-14486 (2007).
194. Mai, A., et al. Design, synthesis, and biological evaluation of sirtinol analogues as class III histone/ protein deacetylase (Sirtuin) inhibitors. J. Med. Chem. 48, 7789-7795 (2005).
195. Grozinger, C. M., Chao, E. D., Blackwell, H. E., Moazed, D., & Schreiber, S. L. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem. 276, 38837-38843 (2001).
196. Tervo, A. J., et al. An in silico approach to discovering novel inhibitors of human sirtuin type 2. J. Med. Chem. 47, 6292-6298 (2004).
197. Smith, B. C., Hallows, W. C., & Denu, J. M. Mechanisms and molecular probes of sirtuins. Chem. Biol. 15, 1002-1013 (2008).
198. Wang, T. T., Schoene, N. W., Kim, E. K., & Kim, Y. S. Pleiotropic effects of the sirtuin inhibitor sirtinol involves concentration-dependent modulation of multiple nuclear receptor-mediated pathways in androgen-responsive prostate cancer cell LNCaP. Mol. Carcinog. 52, 676-685 (2013).
199. Bedalov, A., Gatbonton, T., Irvine, W. P., Gottschling, D. E., & Simon, J. A. Identification of a small molecule inhibitor of Sir2p. Proc. Natl Acad. Sci. USA 98, 15113-15118 (2001).
200. Heltweg, B., et al. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Cancer Res. 66, 4368-4377 (2006).
201. Mahajan, S. S., et al. Development of pyrazolone and isoxazol 5 one cambinol analogues as sirtuin inhibitors. J. Med. Chem. 57, 3283-3294 (2014).
202. Lain, S., et al. Discovery. in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13, 454-463 (2008).
203. Li, L., et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 21, 266-281 (2012).
204. McCarthy, A. R., et al. Tenovin D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53 independent manner. Mol. Cancer Ther. 12, 352-360 (2013).
205. Newbold, A., Salmon, J. M., Martin, B. P., Stanley, K., & Johnstone, R. W. The role of p21waf1/cip1 and p27Kip1 in HDACi-mediated tumor cell death and cell cycle arrest in the Emu-myc model of B cell lymphoma. Oncogene 33, 5415-5423 (2014).
206. Trapp, J., et al. Structure-Activity studies on suramin analogues as inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem 2, 1419-1431 (2007).
207. McGeary, R. P., Bennett, A. J., Tran, Q. B., Cosgrove, K. L., & Ross, B. P. Suramin: clinical uses and structure-Activity relationships. Mini Rev. Med. Chem. 8, 1384-1394 (2008).
208. Small, E. J., et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J. Clin. Oncol. 18, 1440-1450 (2000).
209. Solomon, J. M., et al. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol. Cell. Biol. 26, 28-38 (2006).
210. Outeiro, T. F., et al. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson?s disease. Science 317, 516-519 (2007).
211. Dhalluin, C., et al. Structure and ligand of a histone acetyltransferase bromodomain. Nature 399, 491-496 (1999).
212. Jacobson, R. H., Ladurner, A. G., King, D. S., & Tjian, R. Structure and function of a human TAFII250 double bromodomain module. Science 288, 1422-1425 (2000).
213. Dey, A., Chitsaz, F., Abbasi, A., Misteli, T., & Ozato, K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc. Natl Acad. Sci. USA 100, 8758-8763 (2003).
214. Dey, A., Nishiyama, A., Karpova, T., McNally, J., & Ozato, K. Brd4 marks select genes on mitotic chromatin and directs postmitotic transcription. Mol. Biol. Cell 20, 4899-4909 (2009).
215. Zhao, R., Nakamura, T., Fu, Y., Lazar, Z., & Spector, D. L. Gene bookmarking accelerates the kinetics of post-mitotic transcriptional re activation. Nat. Cell Biol. 13, 1295-1304 (2011).
216. Morinière, J., et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 461, 664-668 (2009).
217. Roe, J. S., Mercan, F., Rivera, K., Pappin, D. J., & Vakoc, C. R. BET bromodomain inhibition suppresses the function of hematopoietic transcription factors in acute myeloid leukemia. Mol. Cell 58, 1028-1039 (2015).
218. French, C. A., et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene 27, 2237-2242 (2008).
219. Filippakopoulos, P., et al. Selective inhibition of BET bromodomains. Nature 468, 1067-1073 (2010).
220. VonVoigtlander, P. F., & Straw, R. N. Alprazolam: review of pharmacological, pharmacokinetic, and clinical data. Drug Dev. Res. 6, 1-12 (1985).
221. Filippakopoulos, P., et al. Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family. Bioorg. Med. Chem. 20, 1878-1886 (2012).
222. Anders, L., et al. Genome-wide localization of small molecules. Nat. Biotechnol. 32, 92-96 (2014).
223. Zuber, J., et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478, 524-528 (2011).
224. Dawson, M. A., et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529-533 (2011).
225. Yang, Z., et al. Recruitment of P TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol. Cell 19, 535-545 (2005).
226. Yang, Z., He, N., & Zhou, Q. Brd4 recruits P TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol. Cell. Biol. 28, 967-976 (2008).
227. Beroukhim, R., et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899-905 (2010).
228. Rahl, P. B., et al. c Myc regulates transcriptional pause release. Cell 141, 432-445 (2010).
229. Delmore, J. E., et al. BET bromodomain inhibition as a therapeutic strategy to target c Myc. Cell 146, 904-917 (2011).
230. Mertz, J. A., et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci. USA 108, 16669-16674 (2011).
231. Ott, C. J., et al. BET bromodomain inhibition targets both c Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood 120, 2843-2852 (2012).
232. Lovén, J., et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320-334 (2013).
233. Dani, C., et al. Extreme instability of myc mRNA in normal and transformed human cells. Proc. Natl Acad. Sci. USA 81, 7046-7050 (1984).
234. Chapuy, B., et al. Discovery and characterization of super-enhancer-Associated dependencies in diffuse large B cell lymphoma. Cancer Cell 24, 777-790 (2013).
235. Zou, Z., et al. Brd4 maintains constitutively active NF kappaB in cancer cells by binding to acetylated RelA. Oncogene 33, 2395-2404 (2014).
236. Lu, J., et al. Hijacking the E3 ubiquitin ligase cereblon to efficiently target BRD4. Chem. Biol. 22, 755-763 (2015).
237. Chung, C. W., et al. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J. Med. Chem. 54, 3827-3838 (2011).
238. Hewings, D. S., et al. 3, 5 Dimethylisoxazoles act as acetyl-lysine-mimetic bromodomain ligands. J. Med. Chem. 54, 6761-6770 (2011).
239. Smith, E., Lin, C., & Shilatifard, A. The super elongation complex (SEC) and MLL in development and disease. Genes Dev. 25, 661-672 (2011).
240. Muntean, A. G., et al. The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell 17, 609-621 (2010).
241. Picaud, S., et al. PFI 1, a highly selective protein interaction inhibitor, targeting BET bromodomains. Cancer Res. 73, 3336-3346 (2013).
242. Ciceri, P., et al. Dual kinase-bromodomain inhibitors for rationally designed polypharmacology. Nat. Chem. Biol. 10, 305-312 (2014).
243. Younes, A., et al. Safety, tolerability, and preliminary activity of CUDC 907, a first in class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 17, 622-631 (2016).
244. Dang, L., Yen, K., & Attar, E. C. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann. Oncol. 27, 599-608 (2016).
245. Isakovic, L., et al. Constrained (l-)-S adenosyl-l homocysteine (SAH) analogues as DNA methyltransferase inhibitors. Bioorg. Med. Chem. Lett. 19, 2742-2746 (2009).
246. Jüttermann, R., Li, E., & Jaenisch, R. Toxicity of 5 aza 2? deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc. Natl Acad. Sci. USA 91, 11797-11801 (1994).
247. Santi, D. V., Garrett, C. E., & Barr, P. J. On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs. Cell 33, 9-10 (1983).
248. Gowher, H., & Jeltsch, A. Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy. Cancer Biol. Ther. 3, 1062-1068 (2004).
249. Li, L. H., Olin, E. J., Buskirk, H. H., & Reineke, L. M. Cytotoxicity and mode of action of 5 azacytidine on L1210 leukemia. Cancer Res. 30, 2760-2769 (1970).
250. Aimiuwu, J., et al. RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5 azacytidine activity in acute myeloid leukemia. Blood 119, 5229-5238 (2012).
251. Schaefer, M., Hagemann, S., Hanna, K., & Lyko, F. Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer Res. 69, 8127-8132 (2009).
252. Kantarjian, H., et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 106, 1794-1803 (2006).
253. Fenaux, P., et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 10, 223-232 (2009).
254. Chuang, J. C., et al. 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, 1443-1450 (2010).
255. Bejar, R., et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124, 2705-2712 (2014).
256. Call, K. M., Jensen, J. C., Liber, H. L., & Thilly, W. G. Studies of mutagenicity and clastogenicity of 5 azacytidine in human lymphoblasts and Salmonella typhimurium. Mutat. Res. 160, 249-257 (1986).
257. Cornacchia, E., et al. Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J. Immunol. 140, 2197-2200 (1988).
258. Kuck, D., Singh, N., Lyko, F., & Medina-Franco, J. L. Novel and selective DNA methyltransferase inhibitors: docking-based virtual screening and experimental evaluation. Bioorg. Med. Chem. 18, 822-829 (2010).
259. Siedlecki, P., et al. Discovery of two novel, small-molecule inhibitors of DNA methylation. J. Med. Chem. 49, 678-683 (2006).
260. Datta, J., et al. A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. Cancer Res. 69, 4277-4285 (2009).
261. Brueckner, B., et al. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res. 65, 6305-6311 (2005).
262. Song, J., Teplova, M., Ishibe-Murakami, S., & Patel, D. J. Structure-based mechanistic insights into DNMT1 mediated maintenance DNA methylation. Science 335, 709-712 (2012).
263. Dubroff, L. M., & Reid, R. J. Jr. Hydralazine-pyrimidine interactions may explain hydralazine-induced lupus erythematosus. Science 208, 404-406 (1980).
264. Lee, B. H., Yegnasubramanian, S., Lin, X., & Nelson, W. G. Procainamide is a specific inhibitor of DNA methyltransferase 1. J. Biol. Chem. 280, 40749-40756 (2005).
265. Segura-Pacheco, B., et al. Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. Clin. Cancer Res. 9, 1596-1603 (2003).
266. Caulfield, T., & Medina-Franco, J. L. Molecular dynamics simulations of human DNA methyltransferase 3B with selective inhibitor nanaomycin A. J. Struct. Biol. 176, 185-191 (2011).
267. Lee, J. S., Smith, E., & Shilatifard, A. The language of histone crosstalk. Cell 142, 682-685 (2010).
268. Santoro, F., et al. A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance. Blood 121, 3459-3468 (2013).
269. Heideman, M. R., et al. Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c Myc collaborating genes and p53 function. Blood 121, 2038-2050 (2013).
270. Goodman, R. H., & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553-1577 (2000).
271. Gu, W., & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C terminal domain. Cell 90, 595-606 (1997).
272. Shiota, M., et al. Tip60 promotes prostate cancer cell proliferation by translocation of androgen receptor into the nucleus. Prostate 70, 540-554 (2010).
273. Gorrini, C., et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448, 1063-1067 (2007).
274. Palumbo, A., et al. Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-Analysis of individual patient data. Lancet Oncol. 15, 333-342 (2014).
275. Falkenberg, K. J., & Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 13, 673-691 (2014).
276. Deardorff, M. A., et al. HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature 489, 313-317 (2012).
277. Wu, J., et al. The up regulation of histone deacetylase 8 promotes proliferation and inhibits apoptosis in hepatocellular carcinoma. Dig. Dis. Sci. 58, 3545-3553 (2013).
278. Wilson, B. J., Tremblay, A. M., Deblois, G., Sylvain-Drolet, G., & Giguère, V. An acetylation switch modulates the transcriptional activity of estrogen-related receptor alpha. Mol. Endocrinol. 24, 1349-1358 (2010).
279. Balasubramanian, S., et al. A novel histone deacetylase 8 (HDAC8)-specific inhibitor PCI 34051 induces apoptosis in T cell lymphomas. Leukemia 22, 1026-1034 (2008).
280. Rettig, I., et al. Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. Cell Death Dis. 6, e1657 (2015).
281. Li, Y., Shin, D., & Kwon, S. H. Histone deacetylase 6 plays a role as a distinct regulator of diverse cellular processes. FEBS J. 280, 775-793 (2013).
282. Bali, P., et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 280, 26729-26734 (2005).
283. Kawaguchi, Y., et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727-738 (2003).
284. Boyault, C., et al. HDAC6 controls major cell response pathways to cytotoxic accumulation of protein aggregates. Genes Dev. 21, 2172-2181 (2007).
285. Haggarty, S. J., Koeller, K. M., Wong, J. C., Grozinger, C. M., & Schreiber, S. L. Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc. Natl Acad. Sci. USA 100, 4389-4394 (2003).
286. Santo, L., et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY 1215, in combination with bortezomib in multiple myeloma. Blood 119, 2579-2589 (2012).
287. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01684150 (2016).
288. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02082977 (2016).
289. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01897571 (2016).
290. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02395601 (2016).
291. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02273102 (2016).
292. US National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02177812 (2016).
293. EU Clinical Trials Register. ClinicalTrialsRegister.eu https://www.clinicaltrialsregister.eu/ctr-search/ trial/2013-002447-29/ES (2013).
294. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01713582 (2016).
295. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01949883 (2016).
296. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02419417 (2016).
297. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01587703 (2016).
298. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02391480 (2016).
299. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02308761 (2016).
300. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02468687 (2016).
301. O?Connor, O. A., et al. Belinostat in patients with relapsed or refractory peripheral T cell lymphoma: results of the pivotal Phase II BELIEF (CLN 19) Study. J. Clin. Oncol. 33, 2492-2499 (2015).
302. San-Miguel, J. F., et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 15, 1195-1206 (2014).