Hostname: page-component-586b7cd67f-2plfb Total loading time: 0 Render date: 2024-11-21T09:07:23.702Z Has data issue: false hasContentIssue false
  • English
  • Français

Small molecule epigenetic inhibitors targeted to histone lysine methyltransferases and demethylases

Published online by Cambridge University Press:  02 September 2013

Zhanxin Wang  and
Dinshaw J. Patel
Zhanxin Wang*
Affiliation:
Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, People's Republic of China Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
Dinshaw J. Patel*
Affiliation:
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
*
Z. Wang, Key Laboratory of Cell Proliferation and Regulation Biology of Ministry of Education, College of Life Sciences, Beijing Normal University, 19 Xinjiekouwai Avenue, Beijing 100875, China. Email: wangz@bnu.edu.cn
*Authors for Correspondence: D. J. Patel, Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Email: pateld@mskcc.org
Get access Rights & Permissions [Opens in a new window]

Abstract

Altered chromatin structures and dynamics are responsible for a range of human malignancies, among which the status of histone lysine methylation remains of paramount importance. Histone lysine methylation is maintained by the relative activities of sequence-specific methyltransferase (KMT) writers and demethylase (KDM) erasers, with aberrant enzymatic activities or expression profiles closely correlated with multiple human diseases. Hence, targeting these epigenetic enzymes should provide a promising avenue for pharmacological intervention of aberrantly marked sites within the epigenome. Here we present an up-to-date critical evaluation on the development and optimization of potent small molecule inhibitors targeted to histone KMTs and KDMs, with the emphasis on contributions of structural biology to development of epigenetic drugs for therapeutic intervention. We anticipate that ongoing advances in the development of epigenetic inhibitors should lead to novel drugs that site-specifically target KMTs and KDMs, key enzymes responsible for maintenance of the lysine methylation landscape in the epigenome.

Type
Review Article
Information
Quarterly Reviews of Biophysics , Volume 46 , Issue 4 , November 2013 , pp. 349 - 373
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

8. References

Arrowsmith, C. H., Bountra, C., Fish, P. V., Lee, K. & Schapira, M. (2012). Epigenetic protein families: a new frontier for drug discovery. Nature Review Drug Discovery 11, 384–400.CrossRefGoogle ScholarPubMed
Beck, D. B., Oda, H., Shen, S. S. & Reinberg, D. (2012). PR-Set7 and H4K20me1: at the crossroads of genome integrity, cell cycle, chromosome condensation, and transcription. Genes and Development 26, 325–337.CrossRefGoogle ScholarPubMed
Benelkebir, H., Hodgkinson, C., Duriez, P. J., Hayden, A. L., Bulleid, R. A., Crabb, S. J., Packham, G. & Ganesan, A. (2011). Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors. Bioorganic and Medical Chemistry 19, 3709–3716.CrossRefGoogle ScholarPubMed
Bernt, K. M., Zhu, N., Sinha, A. U., Vempati, S., Faber, J., Krivtsov, A. V., Feng, Z., Punt, N., Daigle, A., Bullinger, L., Pollock, R. M., Richon, V. M., Kung, A. L. & Armstrong, S. A. (2011). MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78.CrossRefGoogle ScholarPubMed
Binda, C., Valente, S., Romanenghi, M., Pilotto, S., Cirilli, R., Karytinos, A., Ciossani, G., Botrugno, O. A., Forneris, F., Tardugno, M., Edmondson, D. E., Minucci, S., Mattevi, A. & Mai, A. (2010). Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. Journal of the American Chemical Society 132, 6827–6833.CrossRefGoogle ScholarPubMed
Chang, K. H., King, O. N., Tumber, A., Woon, E. C., Heightman, T. D., McDonough, M. A., Schofield, C. J. & Rose, N. R. (2011). Inhibition of histone demethylases by 4-carboxy-2,2′-bipyridyl compounds. ChemMedChem 6, 759–764.CrossRefGoogle Scholar
Chang, Y., Ganesh, T., Horton, J. R., Spannhoff, A., Liu, J., Sun, A., Zhang, X., Bedford, M. T., Shinkai, Y., Snyder, J. P. & Cheng, X. (2010). Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases. Journal of Molecular Biology 400, 1–7.CrossRefGoogle ScholarPubMed
Chang, Y., Zhang, X., Horton, J. R., Upadhyay, A. K., Spannhoff, A., Liu, J., Snyder, J. P., Bedford, M. T. & Cheng, X. (2009). Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294. Nature Structural Molecular Biology 16, 312–317.CrossRefGoogle ScholarPubMed
Chen, M. W., Hua, K. T., Kao, H. J., Chi, C. C., Wei, L. H., Johansson, G., Shiah, S. G., Chen, P. S., Jeng, Y. M., Cheng, T. Y., Lai, T. C., Chang, J. S., Jan, Y. H., Chien, M. H., Yang, C. J., Huang, M. S., Hsiao, M. & Kuo, M. L. (2010). H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Research 70, 7830–7840.CrossRefGoogle ScholarPubMed
Cheng, X., Collins, R. E. & Zhang, X. (2005). Structural and sequence motifs of protein (histone) methylation enzymes. Annual Review of Biophysics and Biomolecular Structure 34, 267–294.CrossRefGoogle ScholarPubMed
Cherblanc, F. L., Chapman, K. L., Brown, R. & Fuchter, M. J. (2013). Chaetocin is a nonspecific inhibitor of histone lysine methyltransferases. Nature Chemical Biology 9, 136–137.CrossRefGoogle ScholarPubMed
Chi, P., Allis, C. D. & Wang, G. G. (2010). Covalent histone modifications – miswritten, misinterpreted and mis-erased in human cancers. Nature Reviews Cancer 10, 457–469.CrossRefGoogle ScholarPubMed
Chiang, P. K. & Cantoni, G. L. (1979). Perturbation of biochemical transmethylations by 3-deazaadenosine in vivo. Biochemical Pharmacology 28, 1897–1902.CrossRefGoogle ScholarPubMed
Chowdhury, R., Yeoh, K. K., Tian, Y. M., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K., Li, X. S., Woon, E. C., Yang, M., McDonough, M. A., King, O. N., Clifton, I. J., Klose, R. J., Claridge, T. D., Ratcliffe, P. J., Schofield, C. J. & Kawamura, A. (2011). The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Reports 12, 463–469.CrossRefGoogle ScholarPubMed
Cloos, P. A., Christensen, J., Agger, K., Maiolica, A., Rappsilber, J., Antal, T., Hansen, K. H. & Helin, K. (2006). The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311.CrossRefGoogle ScholarPubMed
Copeland, R. A., Solomon, M. E. & Richon, V. M. (2009). Protein methyltransferases as a target class for drug discovery. Nature Reviews Drug Discovery 8, 724–732.CrossRefGoogle ScholarPubMed
Couture, J. F., Collazo, E., Ortiz-Tello, P. A., Brunzelle, J. S. & Trievel, R. C. (2007). Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase. Nature Structural and Molecular Biology 14, 689–695.CrossRefGoogle ScholarPubMed
Couture, J. F., Hauk, G., Thompson, M. J., Blackburn, G. M. & Trievel, R. C. (2006). Catalytic roles for carbon-oxygen hydrogen bonding in SET domain lysine methyltransferases. Journal of Biological Chemistry 281, 19280–19287.CrossRefGoogle ScholarPubMed
Crea, F., Sun, L., Mai, A., Chiang, Y. T., Farrar, W. L., Danesi, R. & Helgason, C. D. (2012). The emerging role of histone lysine demethylases in prostate cancer. Molecular Cancer 11, 52.CrossRefGoogle ScholarPubMed
Culhane, J. C., Szewczuk, L. M., Liu, X., Da, G., Marmorstein, R. & Cole, P. A. (2006). A mechanism-based inactivator for histone demethylase LSD1. Journal of the American Chemical Society 128, 4536–4537.CrossRefGoogle ScholarPubMed
Culhane, J. C., Wang, D., Yen, P. M. & Cole, P. A. (2010). Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors. Journal of the American Chemical Society 132, 3164–3176.CrossRefGoogle ScholarPubMed
Daigle, S. R., Olhava, E. J., Therkelsen, C. A., Majer, C. R., Sneeringer, C. J., Song, J., Johnston, L. D., Scott, M. P., Smith, J. J., Xiao, Y., Jin, L., Kuntz, K. W., Chesworth, R., Moyer, M. P., Bernt, K. M., Tseng, J. C., Kung, A. L., Armstrong, S. A., Copeland, R. A., Richon, V. M. & Pollock, R. M. (2011). Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53–65.CrossRefGoogle ScholarPubMed
Dancy, B. C., Ming, S. A., Papazyan, R., Jelinek, C. A., Majumdar, A., Sun, Y., Dancy, B. M., Drury, W. J. 3rd, Cotter, R. J., Taverna, S. D. & Cole, P. A. (2012). Azalysine analogues as probes for protein lysine deacetylation and demethylation. Journal of the American Chemical Society 134, 5138–5148.CrossRefGoogle ScholarPubMed
Dawson, M. A. & Kouzarides, T. (2012). Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27.CrossRefGoogle ScholarPubMed
Dawson, M. A., Kouzarides, T. & Huntly, B. J. (2012). Targeting epigenetic readers in cancer. New England Journal of Medicine 367, 647–657.CrossRefGoogle ScholarPubMed
Eglen, R. M., Reisine, T., Roby, P., Rouleau, N., Illy, C., Bosse, R. & Bielefeld, M. (2008). The use of AlphaScreen technology in HTS: current status. Current Chemical Genomics 1, 2–10.CrossRefGoogle ScholarPubMed
Feng, Q., Wang, H., Ng, H. H., 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. Current Biology 12, 1052–1058.CrossRefGoogle ScholarPubMed
Ferguson, A. D., Larsen, N. A., Howard, T., Pollard, H., Green, I., Grande, C., Cheung, T., Garcia-Arenas, R., Cowen, S., Wu, J., Godin, R., Chen, H. & Keen, N. (2011). Structural basis of substrate methylation and inhibition of SMYD2. Structure 19, 1262–1273.CrossRefGoogle ScholarPubMed
Fierz, B. & Muir, T. W. (2012). Chromatin as an expansive canvas for chemical biology. Nature Chemical Biology 8, 417–427.CrossRefGoogle ScholarPubMed
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. Bioorganic and Medical Chemistry Letters 23, 733–736.CrossRefGoogle ScholarPubMed
Ghosh, S., Nie, A., An, J. & Huang, Z. (2006). Structure-based virtual screening of chemical libraries for drug discovery. Currunt Opinion in Chemical Biology 10, 194–202.CrossRefGoogle ScholarPubMed
Gooden, D. M., Schmidt, D. M., Pollock, J. A., Kabadi, A. M. & McCafferty, D. G. (2008). Facile synthesis of substituted trans-2-arylcyclopropylamine inhibitors of the human histone demethylase LSD1 and monoamine oxidases A and B. Bioorganic and Medical Chemistry Letters 18, 3047–3051.CrossRefGoogle ScholarPubMed
Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. & Imhof, A. (2005). Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9. Nature Chemical Biology 1, 143–145.CrossRefGoogle ScholarPubMed
Grembecka, J., He, S., Shi, A., Purohit, T., Muntean, A. G., Sorenson, R. J., Showalter, H. D., Murai, M. J., Belcher, A. M., Hartley, T., Hess, J. L. & Cierpicki, T. (2012). Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nature Chemical Biology 8, 277–284.CrossRefGoogle ScholarPubMed
Grewal, S. I. & Jia, S. (2007). Heterochromatin revisited. Nature Reviews Genetics 8, 35–46.CrossRefGoogle ScholarPubMed
Hamada, S., Kim, T. D., 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. Bioorganic and Medical Chemistry Letters 19, 2852–2855.CrossRefGoogle ScholarPubMed
Hamada, S., Suzuki, T., Mino, K., Koseki, K., Oehme, F., Flamme, I., Ozasa, H., Itoh, Y., Ogasawara, D., Komaarashi, H., Kato, A., Tsumoto, H., Nakagawa, H., Hasegawa, M., Sasaki, R., Mizukami, T. & Miyata, N. (2010). Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of jumonji domain-containing protein 2 histone demethylase inhibitors. Journal of Medicinal Chemistry 53, 5629–5638.CrossRefGoogle ScholarPubMed
Hardy, J. A. & Wells, J. A. (2004). Searching for new allosteric sites in enzymes. Current Opinion in Structural Biology 14, 706–715.CrossRefGoogle ScholarPubMed
Hazeldine, S., Pachaiyappan, B., Steinbergs, N., Nowotarski, S., Hanson, A. S., Casero, R. A. Jr. & Woster, P. M. (2012). Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1. Journal of Medicinal Chemistry 55, 7378–7391.CrossRefGoogle ScholarPubMed
Huang, J., Gurung, B., Wan, B., Matkar, S., Veniaminova, N. A., Wan, K., Merchant, J. L., Hua, X. & Lei, M. (2012). The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482, 542–546.CrossRefGoogle ScholarPubMed
Huang, Y., Fang, J., Bedford, M. T., Zhang, Y. & Xu, R. M. (2006). Recognition of histone H3 lysine-4 methylation by the double tudor domain of JMJD2A. Science 312, 748–751.CrossRefGoogle ScholarPubMed
Huang, Y., Greene, E., Murray Stewart, T., Goodwin, A. C., Baylin, S. B., Woster, P. M. & Casero, R. A. Jr. (2007). Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes. Proceedings of the National Academy of Sciences USA 104, 8023–8028.CrossRefGoogle ScholarPubMed
Huang, Y., Stewart, T. M., Wu, Y., Baylin, S. B., Marton, L. J., Perkins, B., Jones, R. J., Woster, P. M. & Casero, R. A. Jr. (2009). Novel oligoamine analogues inhibit lysine-specific demethylase 1 and induce reexpression of epigenetically silenced genes. Clinical Cancer Research 15, 7217–7228.CrossRefGoogle ScholarPubMed
Kang, M. Y., Lee, B. B., Kim, Y. H., Chang, D. K., Kyu Park, S., Chun, H. K., Song, S. Y., Park, J. & Kim, D. H. (2007). Association of the SUV39H1 histone methyltransferase with the DNA methyltransferase 1 at mRNA expression level in primary colorectal cancer. International Journal of Cancer 121, 2192–2197.CrossRefGoogle ScholarPubMed
King, O. N., Li, X. S., Sakurai, M., Kawamura, A., Rose, N. R., Ng, S. S., Quinn, A. M., Rai, G., Mott, B. T., Beswick, P., Klose, R. J., Oppermann, U., Jadhav, A., Heightman, T. D., Maloney, D. J., Schofield, C. J. & Simeonov, A. (2010). Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. PLoS One 5, e15535.CrossRefGoogle ScholarPubMed
Knutson, S. K., Wigle, T. J., Warholic, N. M., Sneeringer, C. J., Allain, C. J., Klaus, C. R., Sacks, J. D., Raimondi, A., Majer, C. R., Song, J., Scott, M. P., Jin, L., Smith, J. J., Olhava, E. J., Chesworth, R., Moyer, M. P., Richon, V. M., Copeland, R. A., Keilhack, H., Pollock, R. M. & Kuntz, K. W. (2012). A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature Chemical Biology 8, 890–896.CrossRefGoogle ScholarPubMed
Komatsu, S., Imoto, I., Tsuda, H., Kozaki, K. I., Muramatsu, T., Shimada, Y., Aiko, S., Yoshizumi, Y., Ichikawa, D., Otsuji, E. & Inazawa, J. (2009). Overexpression of SMYD2 relates to tumor cell proliferation and malignant outcome of esophageal squamous cell carcinoma. Carcinogenesis 30, 1139–1146.CrossRefGoogle ScholarPubMed
Krauss, V. (2008). Glimpses of evolution: heterochromatic histone H3K9 methyltransferases left its marks behind. Genetica 133, 93–106.CrossRefGoogle ScholarPubMed
Krivtsov, A. V. & Armstrong, S. A. (2007). MLL translocations, histone modifications and leukaemia stem-cell development. Nature Reviews Cancer 7, 823–833.CrossRefGoogle ScholarPubMed
Kruidenier, L., Chung, C. W., 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, P. K., Mosley, J., Ramirez-Molina, C., Rowland, P., Schofield, C. J., Sheppard, R. J., Smith, J. E., Swales, C., Tanner, R., Thomas, P., Tumber, A., Drewes, G., Oppermann, U., Patel, D. J., Lee, K. & Wilson, D. M. (2012). A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404–408.CrossRefGoogle ScholarPubMed
Kubicek, S., O'Sullivan, R. J., August, E. M., Hickey, E. R., Zhang, Q., Teodoro, M. L., Rea, S., Mechtler, K., Kowalski, J. A., Homon, C. A., Kelly, T. A. & Jenuwein, T. (2007). Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Molecular Cell 25, 473–481.CrossRefGoogle ScholarPubMed
Lee, J., Thompson, J. R., Botuyan, M. V. & Mer, G. (2008). Distinct binding modes specify the recognition of methylated histones H3K4 and H4K20 by JMJD2A-tudor. Nature Structural and Molecular Biology 15, 109–111.CrossRefGoogle ScholarPubMed
Lee, M. G., Wynder, C., Schmidt, D. M., McCafferty, D. G. & Shiekhattar, R. (2006). Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chemical Biology 13, 563–567.CrossRefGoogle ScholarPubMed
Liang, Y., Quenelle, D., Vogel, J. L., Mascaro, C., Ortega, A. & Kristie, T. M. (2013). A Novel Selective LSD1/KDM1A Inhibitor Epigenetically Blocks Herpes Simplex Virus Lytic Replication and Reactivation from Latency. MBio 4, e00558–12.CrossRefGoogle ScholarPubMed
Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 46, 3–26.CrossRefGoogle ScholarPubMed
Liu, F., Chen, X., Allali-Hassani, A., Quinn, A. M., Wigle, T. J., Wasney, G. A., Dong, A., Senisterra, G., Chau, I., Siarheyeva, A., Norris, J. L., Kireev, D. B., Jadhav, A., Herold, J. M., Janzen, W. P., Arrowsmith, C. H., Frye, S. V., Brown, P. J., 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. Journal of Medicinal Chemistry 53, 5844–5857.CrossRefGoogle ScholarPubMed
Lohse, B., Nielsen, A. L., Kristensen, J. B., Helgstrand, C., Cloos, P. A., Olsen, L., Gajhede, M., Clausen, R. P. & Kristensen, J. L. (2011). Targeting histone lysine demethylases by truncating the histone 3 tail to obtain selective substrate-based inhibitors. Angewandte Chemie International Edition English 50, 9100–9103.CrossRefGoogle ScholarPubMed
Luo, X., Liu, Y., Kubicek, S., Myllyharju, J., Tumber, A., Ng, S., Che, K. H., Podoll, J., Heightman, T. D., Oppermann, U., Schreiber, S. L. & Wang, X. (2011). A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases. Journal of the American Chemical Society 133, 9451–9456.CrossRefGoogle ScholarPubMed
Margueron, R. & Reinberg, D. (2011). The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349.CrossRefGoogle ScholarPubMed
McCabe, M. T., Ott, H. M., Ganji, G., Korenchuk, S., Thompson, C., Van Aller, G. S., Liu, Y., Graves, A. P., Della Pietra, A. 3rd, Diaz, E., LaFrance, L. V., Mellinger, M., Duquenne, C., Tian, X., Kruger, R. G., McHugh, C. F., Brandt, M., Miller, W. H., Dhanak, D., Verma, S. K., Tummino, P. J. & Creasy, C. L. (2012). EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108–112.CrossRefGoogle ScholarPubMed
Metzger, E., Wissmann, M., Yin, N., Muller, J. M., Schneider, R., Peters, A. H., Gunther, T., Buettner, R. & Schule, R. (2005). LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439.CrossRefGoogle ScholarPubMed
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, 6494–6503.CrossRefGoogle ScholarPubMed
Min, J., Feng, Q., Li, Z., Zhang, Y. & Xu, R. M. (2003). Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase. Cell 112, 711–723.CrossRefGoogle ScholarPubMed
Minucci, S. & Pelicci, P. G. (2006). Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Reviews in Cancer 6, 38–51.CrossRefGoogle ScholarPubMed
Miranda, T. B., Cortez, C. C., Yoo, C. B., Liang, G., Abe, M., Kelly, T. K., Marquez, V. E. & Jones, P. A. (2009). DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. Molecular Cancer Therapeutics 8, 1579–1588.CrossRefGoogle Scholar
Murray, C. W. & Blundell, T. L. (2010). Structural biology in fragment-based drug design. Current Opinion in Structural Biology 20, 497–507.CrossRefGoogle ScholarPubMed
Ng, S. S., Kavanagh, K. L., McDonough, M. A., Butler, D., Pilka, E. S., Lienard, B. M., Bray, J. E., Savitsky, P., Gileadi, O., von Delft, F., Rose, N. R., Offer, J., Scheinost, J. C., Borowski, T., Sundstrom, M., Schofield, C. J. & Oppermann, U. (2007). Crystal structures of histone demethylase JMJD2A reveal basis for substrate specificity. Nature 448, 87–91.CrossRefGoogle ScholarPubMed
Nguyen, A. T. & Zhang, Y. (2011). The diverse functions of Dot1 and H3K79 methylation. Genes and Development 25, 1345–1358.CrossRefGoogle ScholarPubMed
Nielsen, A. L., Kristensen, L. H., Stephansen, K. B., Kristensen, J. B., Helgstrand, C., Lees, M., Cloos, P., Helin, K., Gajhede, M. & Olsen, L. (2012). Identification of catechols as histone-lysine demethylase inhibitors. FEBS Letters 586, 1190–1194.CrossRefGoogle ScholarPubMed
Ogasawara, D., Suzuki, T., Mino, K., Ueda, R., Khan, M. N., Matsubara, T., Koseki, K., Hasegawa, M., Sasaki, R., Nakagawa, H., Mizukami, T. & Miyata, N. (2011). Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor. Bioorganic and Medical Chemistry Letters 19, 3702–3708.CrossRefGoogle ScholarPubMed
Patel, A., Vought, V. E., Dharmarajan, V. & Cosgrove, M. S. (2008). A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex. Journal of Biological Chemistry 283, 32162–32175.CrossRefGoogle ScholarPubMed
Pedersen, M. T. & Helin, K. (2010). Histone demethylases in development and disease. Trends in Cell Biology 20, 662–671.CrossRefGoogle ScholarPubMed
Qi, W., Chan, H., Teng, L., Li, L., Chuai, S., Zhang, R., Zeng, J., Li, M., Fan, H., Lin, Y., Gu, J., Ardayfio, O., Zhang, J. H., Yan, X., Fang, J., Mi, Y., Zhang, M., Zhou, T., Feng, G., Chen, Z., Li, G., Yang, T., Zhao, K., Liu, X., Yu, Z., Lu, C. X., Atadja, P. & Li, E. (2012). Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proceedings of the National Academy of Sciences USA 109, 21360–21365.CrossRefGoogle ScholarPubMed
Rooney, P. H., Murray, G. I., Stevenson, D. A., Haites, N. E., Cassidy, J. & McLeod, H. L. (1999). Comparative genomic hybridization and chromosomal instability in solid tumours. British Journal of Cancer 80, 862–873.CrossRefGoogle ScholarPubMed
Rose, N. R., Ng, S. S., Mecinovic, J., Lienard, B. M., Bello, S. H., Sun, Z., McDonough, M. A., Oppermann, U. & Schofield, C. J. (2008). Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. Journal of Medicinal Chemistry 51, 7053–7056.CrossRefGoogle ScholarPubMed
Rose, N. R., Woon, E. C., Kingham, G. L., King, O. N., Mecinovic, J., Clifton, I. J., Ng, S. S., Talib-Hardy, J., Oppermann, U., McDonough, M. A. & Schofield, C. J. (2010). Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches. Journal of Medicinal Chemistry 53, 1810–1818.CrossRefGoogle ScholarPubMed
Rose, N. R., Woon, E. C., Tumber, A., Walport, L. J., Chowdhury, R., Li, X. S., King, O. N., Lejeune, C., Ng, S. S., Krojer, T., Chan, M. C., Rydzik, A. M., Hopkinson, R. J., Che, K. H., Daniel, M., Strain-Damerell, C., Gileadi, C., Kochan, G., Leung, I. K., Dunford, J., Yeoh, K. K., Ratcliffe, P. J., Burgess-Brown, N., von Delft, F., Muller, S., Marsden, B., Brennan, P. E., McDonough, M. A., Oppermann, U., Klose, R. J., Schofield, C. J. & Kawamura, A. (2012). Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases. Journal of Medicinal Chemistry 55, 6639–6643.CrossRefGoogle ScholarPubMed
Ruthenburg, A. J., Allis, C. D. & Wysocka, J. (2007). Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Molecular Cell 25, 15–30.CrossRefGoogle Scholar
Sakurai, M., Rose, N. R., Schultz, L., Quinn, A. M., Jadhav, A., Ng, S. S., Oppermann, U., Schofield, C. J. & Simeonov, A. (2010). A miniaturized screen for inhibitors of Jumonji histone demethylases. Molecular Biosystems 6, 357–364.CrossRefGoogle ScholarPubMed
Sawada, K., Yang, Z., Horton, J. R., Collins, R. E., Zhang, X. & Cheng, X. (2004). Structure of the conserved core of the yeast Dot1p, a nucleosomal histone H3 lysine 79 methyltransferase. Journal of Biological Chemistry 279, 43296–43306.CrossRefGoogle ScholarPubMed
Sayegh, J., Cao, J., Zou, M. R., Morales, A., Blair, L. P., Norcia, M., Hoyer, D., Tackett, A. J., Merkel, J. S. & Yan, Q. (2013). Identification of small molecule inhibitors of Jumonji AT-Rich interactive domain 1B (JARID1B) histone demethylase by a sensitive high-throughput screen. Journal of Biological Chemistry 288, 9408–9417.CrossRefGoogle ScholarPubMed
Schmidt, D. M. & McCafferty, D. G. (2007). trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46, 4408–4416.CrossRefGoogle ScholarPubMed
Sekirnik, R., Rose, N. R., Thalhammer, A., Seden, P. T., Mecinovic, J. & Schofield, C. J. (2009). Inhibition of the histone lysine demethylase JMJD2A by ejection of structural Zn(II). Chemical Communications 6376–6378.CrossRefGoogle ScholarPubMed
Senisterra, G., Wu, H., Allali-Hassani, A., Wasney, G. A., Barsyte-Lovejoy, D., Dombrovski, L., Dong, A., Nguyen, K. T., Smil, D., Bolshan, Y., Hajian, T., He, H., Seitova, A., Chau, I., Li, F., Poda, G., Couture, J. F., Brown, P. J., Al-Awar, R., Schapira, M., Arrowsmith, C. H. & Vedadi, M. (2013). Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5. Biochemical Journal 449, 151–159.CrossRefGoogle ScholarPubMed
Sharma, S. K., Wu, Y., Steinbergs, N., Crowley, M. L., Hanson, A. S., Casero, R. A. & Woster, P. M. (2010). (Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. Journal of Medicinal Chemistry 53, 5197–5212.CrossRefGoogle ScholarPubMed
Shi, A., Murai, M. J., He, S., Lund, G., Hartley, T., Purohit, T., Reddy, G., Chruszcz, M., Grembecka, J. & Cierpicki, T. (2012). Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia. Blood 120, 4461–4469.CrossRefGoogle ScholarPubMed
Shi, Y. (2007). Histone lysine demethylases: emerging roles in development, physiology and disease. Nature Reviews Genetics 8, 829–833.CrossRefGoogle ScholarPubMed
Shi, Y., Lan, F., Matson, C., Mulligan, P., Whetstine, J. R., Cole, P. A. & Casero, R. A. (2004). Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953.CrossRefGoogle ScholarPubMed
Shih, A. H., Abdel-Wahab, O., Patel, J. P. & Levine, R. L. (2012). The role of mutations in epigenetic regulators in myeloid malignancies. Nature Reviews Cancer 12, 599–612.CrossRefGoogle ScholarPubMed
Siarheyeva, A., Senisterra, G., Allali-Hassani, A., Dong, A., Dobrovetsky, E., Wasney, G. A., Chau, I., Marcellus, R., Hajian, T., Liu, F., Korboukh, I., Smil, D., Bolshan, Y., Min, J., Wu, H., Zeng, H., Loppnau, P., Poda, G., Griffin, C., Aman, A., Brown, P. J., Jin, J., Al-Awar, R., Arrowsmith, C. H., Schapira, M. & Vedadi, M. (2012). An allosteric inhibitor of protein arginine methyltransferase 3. Structure 20, 1425–1435.CrossRefGoogle ScholarPubMed
Suzuki, T. & Miyata, N. (2011). Lysine demethylases inhibitors. Journal of Medicinal Chemistry 54, 8236–8250.CrossRefGoogle ScholarPubMed
Szewczuk, L. M., Culhane, J. C., Yang, M., Majumdar, A., Yu, H. & Cole, P. A. (2007). Mechanistic analysis of a suicide inactivator of histone demethylase LSD1. Biochemistry 46, 6892–6902.CrossRefGoogle ScholarPubMed
Szyf, M. (2009). Epigenetics, DNA methylation, and chromatin modifying drugs. Annual Review of Pharmacology and Toxicology 49, 243–263.CrossRefGoogle ScholarPubMed
Tan, J., Yang, X., Zhuang, L., Jiang, X., Chen, W., Lee, P. L., Karuturi, R. K., Tan, P. B., Liu, E. T. & Yu, Q. (2007). Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes and Development 21, 1050–1063.CrossRefGoogle ScholarPubMed
Thalhammer, A., Mecinovic, J., Loenarz, C., Tumber, A., Rose, N. R., Heightman, T. D. & Schofield, C. J. (2011). Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates. Organic and Biomolecular Chemistry 9, 127–135.CrossRefGoogle ScholarPubMed
Tsukada, Y., Fang, J., Erdjument-Bromage, H., Warren, M. E., Borchers, C. H., Tempst, P. & Zhang, Y. (2006). Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816.CrossRefGoogle ScholarPubMed
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. Journal of the American Chemical Society 131, 17536–17537.CrossRefGoogle ScholarPubMed
Vedadi, M., Barsyte-Lovejoy, D., Liu, F., Rival-Gervier, S., Allali-Hassani, A., Labrie, V., Wigle, T. J., Dimaggio, P. A., Wasney, G. A., Siarheyeva, A., Dong, A., Tempel, W., Wang, S. C., Chen, X., Chau, I., Mangano, T. J., Huang, X. P., Simpson, C. D., Pattenden, S. G., Norris, J. L., Kireev, D. B., Tripathy, A., Edwards, A., Roth, B. L., Janzen, W. P., Garcia, B. A., Petronis, A., Ellis, J., Brown, P. J., Frye, S. V., Arrowsmith, C. H. & Jin, J. (2011). A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells. Nature Chemical Biology 7, 566–574.CrossRefGoogle ScholarPubMed
Wagner, E. J. & Carpenter, P. B. (2012). Understanding the language of Lys36 methylation at histone H3. Nature Reviews in Molecular Cell Biology 13, 115–126.CrossRefGoogle ScholarPubMed
Wang, J., Lu, F., Ren, Q., Sun, H., Xu, Z., Lan, R., Liu, Y., Ward, D., Quan, J., Ye, T. & Zhang, H. (2011). Novel histone demethylase LSD1 inhibitors selectively target cancer cells with pluripotent stem cell properties. Cancer Research 71, 7238–7249.CrossRefGoogle ScholarPubMed
Wang, Z., Song, J., Milne, T. A., Wang, G. G., Li, H., Allis, C. D. & Patel, D. J. (2010). Pro isomerization in MLL1 PHD3-bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression. Cell 141, 1183–1194.CrossRefGoogle ScholarPubMed
Williams, D. E., Dalisay, D. S., Li, F., Amphlett, J., Maneerat, W., Chavez, M. A., Wang, Y. A., Matainaho, T., Yu, W., Brown, P. J., Arrowsmith, C. H., Vedadi, M. & Andersen, R. J. (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. Organic Letters 15, 414–417.CrossRefGoogle ScholarPubMed
Woon, E. C., Tumber, A., Kawamura, A., Hillringhaus, L., Ge, W., Rose, N. R., Ma, J. H., Chan, M. C., Walport, L. J., Che, K. H., Ng, S. S., Marsden, B. D., Oppermann, U., McDonough, M. A. & Schofield, C. J. (2012). Linking of 2-oxoglutarate and substrate binding sites enables potent and highly selective inhibition of JmjC histone demethylases. Angewandte Chemie International Edition English 51, 1631–1634.CrossRefGoogle ScholarPubMed
Yang, M., Culhane, J. C., Szewczuk, L. M., Gocke, C. B., Brautigam, C. A., Tomchick, D. R., Machius, M., Cole, P. A. & Yu, H. (2007a). Structural basis of histone demethylation by LSD1 revealed by suicide inactivation. Nature Structural and Molecular Biology 14, 535–539.CrossRefGoogle ScholarPubMed
Yang, M., Culhane, J. C., Szewczuk, L. M., Jalili, P., Ball, H. L., Machius, M., Cole, P. A. & Yu, H. (2007b). Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry 46, 8058–8065.CrossRefGoogle ScholarPubMed
Yao, Y., Chen, P., Diao, J., Cheng, G., Deng, L., Anglin, J. L., Prasad, B. V. & Song, Y. (2011). Selective inhibitors of histone methyltransferase DOT1L: design, synthesis, and crystallographic studies. Journal of the American Chemical Society 133, 16746–16749.CrossRefGoogle ScholarPubMed
Yokoyama, A., Somervaille, T. C., Smith, K. S., Rozenblatt-Rosen, O., Meyerson, M. & Cleary, M. L. (2005). The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123, 207–218.CrossRefGoogle ScholarPubMed
Yu, W., Chory, E. J., Wernimont, A. K., Tempel, W., Scopton, A., Federation, A., Marineau, J. J., Qi, J., Barsyte-Lovejoy, D., Yi, J., Marcellus, R., Iacob, R. E., Engen, J. R., Griffin, C., Aman, A., Wienholds, E., Li, F., Pineda, J., Estiu, G., Shatseva, T., Hajian, T., Al-Awar, R., Dick, J. E., Vedadi, M., Brown, P. J., Arrowsmith, C. H., Bradner, J. E. & Schapira, M. (2012). Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nature Communications 3, 1288.CrossRefGoogle ScholarPubMed
Yu, W., Smil, D., Li, F., Tempel, W., Fedorov, O., Nguyen, K. T., Bolshan, Y., Al-Awar, R., Knapp, S., Arrowsmith, C. H., Vedadi, M., Brown, P. J. & Schapira, M. (2013). Bromo-deaza-SAH: A potent and selective DOT1L inhibitor. Bioorganic and Medicinal Chemistry 21, 1787–1794.CrossRefGoogle ScholarPubMed
Yuan, Y., Wang, Q., Paulk, J., Kubicek, S., Kemp, M. M., Adams, D. J., Shamji, A. F., Wagner, B. K. & Schreiber, S. L. (2012). A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chemical Biology 7, 1152–1157.CrossRefGoogle ScholarPubMed
Zhang, P., Lee, H., Brunzelle, J. S. & Couture, J. F. (2012). The plasticity of WDR5 peptide-binding cleft enables the binding of the SET1 family of histone methyltransferases. Nucleic Acids Research 40, 4237–4246.CrossRefGoogle ScholarPubMed
Zheng, W., Ibanez, G., Wu, H., Blum, G., Zeng, H., Dong, A., Li, F., Hajian, T., Allali-Hassani, A., Amaya, M. F., Siarheyeva, A., Yu, W., Brown, P. J., Schapira, M., Vedadi, M., Min, J. & Luo, M. (2012). Sinefungin derivatives as inhibitors and structure probes of protein lysine methyltransferase SETD2. Journal of the American Chemical Society 134, 18004–18014.CrossRefGoogle ScholarPubMed