REVIEWS Med.Chem 5 38201I- 165.Herold.J.M.et or Med 144 68076 166. 187 200 146. 31-339201 2010. 70.364 M.K . 16 1 200 ,55 149 170 3e4-377o10 200 15 D.cta 2-S15) tep lung 91 ed t p16 and acti n I7S.2007) 。 VM.al 0P01 bro the C optical 62012 nd the Welic or.Bioorg.Med.Chem .370 1 aria.J. .Med. 25,84- 2007 FURTHER INFO 15 G.A.Ron 58 gA⊥iH.PatD.J.&ACD 2.721-7282003 180 t al 083-99480 8 (0 182 16 185 000 ACTIVE IN THE ONL NE PD 00 MAY 2012 VOLUME 1 nature.com/reviews/drugdisc 2012 Macmillan Publishers Limited.All rightsresevd 143. Greiner, D., Bonaldi, T., Eskeland, R., Roemer, E. & Imhof, A. Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3–9. Nature Chem. Biol. 1, 143–145 (2005). 144. Couture, J. F., Hauk, G., Thompson, M. J., Blackburn, G. M. & Trievel, R. C. Catalytic roles for carbon-oxygen hydrogen bonding in SET domain lysine methyltransferases. J. Biol. Chem. 281, 19280–19287 (2006). 145. Campagna-Slater, V. et al. Structural chemistry of the histone methyltransferases cofactor binding site. J. Chem. Inf. Model 51, 612–623 (2011). 146. Sack, J. S. et al. Structural basis for CARM1 inhibition by indole and pyrazole inhibitors. Biochem. J. 436, 331–339 (2011). 147. Dowden, J., Hong, W., Parry, R. V., Pike, R. A. & Ward, S. G. Toward the development of potent and selective bisubstrate inhibitors of protein arginine methyltransferases. Bioorg. Med. Chem. Lett. 20, 2103–2105 (2010). 148. Cheng, D. et al. Small molecule regulators of protein arginine methyltransferases. J. Biol. Chem. 279, 23892–23899 (2004). 149. Culhane, J. C., Wang, D., Yen, P. M. & Cole, P. A. Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors. J. Am. Chem. Soc. 132, 3164–3176 (2010). 150. Schmidt, D. M. & McCafferty, D. G. trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46, 4408–4416 (2007). 151. Mimasu, S. et al. Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1. Biochemistry 49, 6494–6503 (2010). 152. 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). 153. Ogasawara, D. et al. Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor. Bioorg. Med. Chem. 19, 3702–3708 (2011). 154. Ortega Muñoz, A., Castro-Palomino-Laria, J. & Fyfe, M. C. T. Lysine specific demethylase-1 inhibitors and their use. Patent WO2011035941A1 (2011). 155. Rose, N. R. et al. Inhibitor scaffolds for 2-oxoglutarate￾dependent histone lysine demethylases. J. Med. Chem. 51, 7053–7056 (2008). 156. 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). 157. Chang, K. H. et al. Inhibition of histone demethylases by 4-carboxy-2,2′-bipyridyl compounds. ChemMedChem 6, 759–764 (2011). 158. King, O. N. et al. Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. PLoS ONE 5, e15535 (2010). 159. Ruthenburg, A. J., Li, H., Patel, D. J. & Allis, C. D. Multivalent engagement of chromatin modifications by linked binding modules. Nature Rev. Mol. Cell Biol. 8, 983–994 (2007). 160. 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. Nature Struct. Mol. Biol. 14, 1025–1040 (2007). 161. 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). 162. Zeng, L. et al. Selective small molecules blocking HIV-1 Tat and coactivator PCAF association. J. Am. Chem. Soc. 127, 2376–2377 (2005). 163. Borah, J. C. et al. A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes. Chem. Biol. 18, 531–541 (2011). 164. Chung, C. W. et al. Discovery and characterization of small molecule inhibitors of the BET family bromodomains. J. Med. Chem. 54, 3827–3838 (2011). 165. Herold, J. M. et al. Small-molecule ligands of methyl-lysine binding proteins. J. Med. Chem. 54, 2504–2511 (2011). This was the first demonstration that methyl-lysine binding pockets can be antagonized using small molecules. 166. Best, J. D. & Carey, N. Epigenetic opportunities and challenges in cancer. Drug Discov. Today 15, 65–70 (2010). 167. Best, J. D. & Carey, N. Epigenetic therapies for non-oncology indications. Drug Discov. Today 15, 1008–1014 (2010). 168. Anway, M. D., Cupp, A. S., Uzumcu, M. & Skinner, M. K. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005). 169. Anway, M. D., Leathers, C. & Skinner, M. K. Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147, 5515–5523 (2006). 170. Bertram, C. et al. Transgenerational effects of prenatal nutrient restriction on cardiovascular and hypothalamic-pituitary-adrenal function. J. Physiol. 586, 2217–2229 (2008). 171. Brower, V. Epigenetics: unravelling the cancer code. Nature 471, S12–S13 (2011). 172. Blanco, D. et al. Molecular analysis of a multistep lung cancer model induced by chronic inflammation reveals epigenetic regulation of p16 and activation of the DNA damage response pathway. Neoplasia 9, 840–852 (2007). 173. Richon, V. M. et al. Chemogenetic analysis of human protein methyltransferases. Chem. Biol. Drug Des. 78, 199–210 (2011). 174. Bamborough, P. et al. Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides. J. Med. Chem. 55, 587–596 (2012). 175. Medda, F. et al. Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity. J. Med. Chem. 52, 2673–2682 (2009). 176. Marks, P. A. & Breslow, R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nature Biotech. 25, 84–90 (2007). 177. Bertino, E. M. & Otterson, G. A. Romidepsin: a novel histone deacetylase inhibitor for cancer. Expert Opin. Investig. Drugs 20, 1151–1158 (2011). 178. Zhou, Q., Atadja, P. & Davidson, N. E. Histone deacetylase inhibitor LBH589 reactivates silenced estrogen receptor α (ER) gene expression without loss of DNA hypermethylation. Cancer Biol. Ther. 6, 64–69 (2007). 179. Plumb, J. A. et al. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol. Cancer Ther. 2, 721–728 (2003). 180. Hu, E. et al. Identification of novel isoform-selective inhibitors within class I histone deacetylases. J. Pharmacol. Exp. Ther. 307, 720–728 (2003). 181. Fournel, M. et al. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol. Cancer Ther. 7, 759–768 (2008). 182. Younes, A. et al. Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, Phase 2 trial. Lancet Oncol. 12, 1222–1228 (2011). 183. Mandl-Weber, S. et al. The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br. J. Haematol. 149, 518–528 (2010). 184. Furlan, A. et al. Pharmacokinetics, safety and inducible cytokine responses during a Phase 1 trial of the oral histone deacetylase inhibitor ITF2357 (givinostat). Mol. Med. 17, 353–362 (2011). 185. Wang, H. et al. Discovery of (2E)-3-{2-butyl-1-[2- (diethylamino)ethyl]-1H-benzimidazol-5-yl}-N-hydroxya crylamide (SB939), an orally active histone deacetylase inhibitor with a superior preclinical profile. J. Med. Chem. 54, 4694–4720 (2011). 186. Novotny-Diermayr, V. et al. SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. Mol. Cancer Ther. 9, 642–652 (2010). 187. Lai, C. J. et al. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity. Cancer Res. 70, 3647–3656 (2010). 188. Rivera-Del Valle, N. et al. PCI-24781, a novel hydroxamic acid HDAC inhibitor, exerts cytotoxicity and histone alterations via caspase-8 and FADD in leukemia cells. Int. J. Cell Biol. 2010, 207420 (2010). 189. Lucas, D. M. et al. The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-cell malignancies in vitro and in vivo. PLoS ONE 5, e10941 (2010). 190. Hwang, J. J. et al. A novel histone deacetylase inhibitor, CG200745, potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1 and Bcl-(XL). Invest. New Drugs 20 Jul 2011 (doi:10.1007/s10637-011-9718-1). 191. Rosato, R. R. HDAC inhibitors — CHI’s third annual conference. IDrugs 13, 13–15 (2010). Acknowledgements We are grateful to P. Brennan for his contribution on demeth￾ylase inhibitors, and S. Knapp for his comments on the man￾uscript. The Structural Genomics Consortium is a registered charity (charity number 1097737) that receives funds from the Canadian Institutes of Health Research, Eli Lilly, Genome Canada (through the Ontario Genomics Institute), Glaxo￾SmithKline, the Ontario Ministry for Research and Innovation, the Novartis Research Foundation, Pfizer and the Wellcome  Trust. Competing interests statement The authors declare competing financial interests: see Web version for details. FURTHER INFORMATION ClinicalTrials.gov website: http://www.clinicaltrials.gov EnVivo Pharmaceuticals website — Pipeline & Programs: http://www.envivopharma.com/pipeline.php Pfam protein family database: http://pfam.sanger.ac.uk RCSB Protein Data Bank website: http://www.rcsb.org RepliGen website (RG2833: Potential to Alter the Course of Friedreich’s Ataxia): http://www.repligen.com/products/pipeline/rg2833 Siena Biotech website — Development Pipeline: http://www.sienabiotech.it/index.jsp SMART (Simple Modular Architecture Research Tool) database: http://smart.embl-heidelberg.de Structural Genomics Consortium (Annotated Phylogenetic Trees): http://www.thesgc.org/phylogenetic_trees/ Structural Genomics Consortium (Chemical Probes): http://www.thesgc.org/chemical_probes/ Structural Genomics Consortium (Epigenetics: Chemical Probes for Drug Discovery): http://www.thesgc.org/epigenetics/ Structural Genomics Consortium (Histone Tails): http://www.thesgc.org/histone_tails/ SUPPLEMENTARY INFORMATION See online article: S1 (table) | S2 (table) | S3 (table) | S4 (table) | S5 (table) | S6 (table) | S7 (table) | S8 (table) | S9 (table) | S10 (table) | S11 (figure) | S12 (figure) | S13 (figure) | S14 (figure) ALL LINKS ARE ACTIVE IN THE ONLINE PDF REVIEWS 400 | MAY 2012 | VOLUME 11 www.nature.com/reviews/drugdisc © 2012 Macmillan Publishers Limited. All rights reserved