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50. Kruidenier L, Chung C, Cheng Z et al (2012) A selective Jumonji H3K27 demethylase inhibitor
modulates the proinflammatory macrophage response. Nature 488:404–408. https://doi.org/10.
1038/nature11262
51. Jones SE, Olsen L, Gajhede M (2018) Structural basis of histone demethylase KDM6B histone
3 lysine 27 specificity. Biochemistry 57:585–592. https://doi.org/10.1021/acs.biochem.
7b01152
52. Hausinger RP (2004) FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes.
Crit Rev Biochem Mol Biol 39:21–68
53. Horton JR, Liu X, Wu L et al (2018) Insights into the action of inhibitor enantiomers against
histone lysine demethylase 5A. J Med Chem 61:3193. https://doi.org/10.1021/acs.jmedchem.
8b00261
54. Klein BJ, Piao L, Xi Y et al (2014) The histone-H3K4-specific demethylase KDM5B binds to
its substrate and product through distinct PHD fingers. Cell Rep 6:325–335. https://doi.org/10.
1016/j.celrep.2013.12.021
55. Pack LR, Yamamoto KR, Fujimori DG (2016) Opposing chromatin signals direct and regulate
the activity of lysine demethylase 4C (KDM4C). J Biol Chem 291:6060–6070. https://doi.org/
10.1074/jbc.M115.696864
56. Zhang Y, Yang H, Guo X et al (2014) The PHD1 finger of KDM5B recognizes unmodified
H3K4 during the demethylation of histone H3K4me2/3 by KDM5B. Protein Cell 5:837–850.
https://doi.org/10.1007/s13238-014-0078-4
57. Rose NR, Ng SS, Mecinović J et al (2008) Inhibitor scaffolds for 2-oxoglutarate-dependent
histone lysine demethylases. J Med Chem 51:7053–7056. https://doi.org/10.1021/jm800936s
58. Joberty G, Boesche M, Brown JA et al (2016) Interrogating the druggability of the
2-oxoglutarate-dependent dioxygenase target class by chemical proteomics. ACS Chem Biol
11:2002–2010. https://doi.org/10.1021/acschembio.6b00080
59. Kaniskan HÜ, Martini ML, Jin J (2017) Inhibitors of protein methyltransferases and
demethylases. Chem Rev 118:989–1068. https://doi.org/10.1021/acs.chemrev.6b00801
60. McAllister TE, England KS, Hopkinson RJ et al (2016) Recent progress in histone demethylase
inhibitors. J Med Chem 59:1308–1329. https://doi.org/10.1021/acs.jmedchem.5b01758
61. Westaway SM, Preston AGS, Barker MD et al (2015) Cell penetrant inhibitors of the KDM4
and KDM5 families of histone lysine demethylases. 1. 3 – Amino-4-pyridine carboxylate
derivatives. J Med Chem 59:1370–1387. https://doi.org/10.1021/acs.jmedchem.5b01537
62. Chen YK, Bonaldi T, Cuomo A et al (2017) Design of KDM4 inhibitors with antiproliferative
effects in cancer mModels. ACS Med Chem Lett 8:869–874. https://doi.org/10.1021/
acsmedchemlett.7b00220
63. Johansson C, Velupillai S, Tumber A et al (2016) Structural analysis of human KDM5B guides
histone demethylase inhibitor development. Nat Chem Biol 12:1–10. https://doi.org/10.1038/
nchembio.2087
64. Tumber A, Nuzzi A, Hookway ES et al (2018) Potent and selective KDM5 inhibitor stops
cellular demethylation of H3K4me3 at transcription start sites and proliferation of MM1S
myeloma cells. Cell Chem Biol 24:371–380. https://doi.org/10.1016/j.chembiol.2017.02.006
65. Horton JR, Liu X, Gale M et al (2016) Structural basis for KDM5A histone lysine demethylase
inhibition by diverse compounds. Cell Chem Biol 23:213–221. https://doi.org/10.1016/j.
chembiol.2016.06.006
66. Westaway SM, Preston AGS, Barker MD et al (2016) Cell penetrant inhibitors of the KDM4
and KDM5 families of histone lysine demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one
derivatives. J Med Chem 59:1370–1387. https://doi.org/10.1021/acs.jmedchem.5b01538
67. Bavetsias V, Lanigan RM, Ruda GF et al (2016) 8-substituted pyrido[3,4-d]pyrimidin-4(3H)one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine
demethylase inhibitors. J Med Chem 59:1388. https://doi.org/10.1021/acs.jmedchem.5b01635
252
M. Wright et al.
UTX/KDM6A. Genes Dev 25:2266–2277. https://doi.org/10.1101/gad.172296.111
50. Kruidenier L, Chung C, Cheng Z et al (2012) A selective Jumonji H3K27 demethylase inhibitor
modulates the proinflammatory macrophage response. Nature 488:404–408. https://doi.org/10.
1038/nature11262
51. Jones SE, Olsen L, Gajhede M (2018) Structural basis of histone demethylase KDM6B histone
3 lysine 27 specificity. Biochemistry 57:585–592. https://doi.org/10.1021/acs.biochem.
7b01152
52. Hausinger RP (2004) FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes.
Crit Rev Biochem Mol Biol 39:21–68
53. Horton JR, Liu X, Wu L et al (2018) Insights into the action of inhibitor enantiomers against
histone lysine demethylase 5A. J Med Chem 61:3193. https://doi.org/10.1021/acs.jmedchem.
8b00261
54. Klein BJ, Piao L, Xi Y et al (2014) The histone-H3K4-specific demethylase KDM5B binds to
its substrate and product through distinct PHD fingers. Cell Rep 6:325–335. https://doi.org/10.
1016/j.celrep.2013.12.021
55. Pack LR, Yamamoto KR, Fujimori DG (2016) Opposing chromatin signals direct and regulate
the activity of lysine demethylase 4C (KDM4C). J Biol Chem 291:6060–6070. https://doi.org/
10.1074/jbc.M115.696864
56. Zhang Y, Yang H, Guo X et al (2014) The PHD1 finger of KDM5B recognizes unmodified
H3K4 during the demethylation of histone H3K4me2/3 by KDM5B. Protein Cell 5:837–850.
https://doi.org/10.1007/s13238-014-0078-4
57. Rose NR, Ng SS, Mecinović J et al (2008) Inhibitor scaffolds for 2-oxoglutarate-dependent
histone lysine demethylases. J Med Chem 51:7053–7056. https://doi.org/10.1021/jm800936s
58. Joberty G, Boesche M, Brown JA et al (2016) Interrogating the druggability of the
2-oxoglutarate-dependent dioxygenase target class by chemical proteomics. ACS Chem Biol
11:2002–2010. https://doi.org/10.1021/acschembio.6b00080
59. Kaniskan HÜ, Martini ML, Jin J (2017) Inhibitors of protein methyltransferases and
demethylases. Chem Rev 118:989–1068. https://doi.org/10.1021/acs.chemrev.6b00801
60. McAllister TE, England KS, Hopkinson RJ et al (2016) Recent progress in histone demethylase
inhibitors. J Med Chem 59:1308–1329. https://doi.org/10.1021/acs.jmedchem.5b01758
61. Westaway SM, Preston AGS, Barker MD et al (2015) Cell penetrant inhibitors of the KDM4
and KDM5 families of histone lysine demethylases. 1. 3 – Amino-4-pyridine carboxylate
derivatives. J Med Chem 59:1370–1387. https://doi.org/10.1021/acs.jmedchem.5b01537
62. Chen YK, Bonaldi T, Cuomo A et al (2017) Design of KDM4 inhibitors with antiproliferative
effects in cancer mModels. ACS Med Chem Lett 8:869–874. https://doi.org/10.1021/
acsmedchemlett.7b00220
63. Johansson C, Velupillai S, Tumber A et al (2016) Structural analysis of human KDM5B guides
histone demethylase inhibitor development. Nat Chem Biol 12:1–10. https://doi.org/10.1038/
nchembio.2087
64. Tumber A, Nuzzi A, Hookway ES et al (2018) Potent and selective KDM5 inhibitor stops
cellular demethylation of H3K4me3 at transcription start sites and proliferation of MM1S
myeloma cells. Cell Chem Biol 24:371–380. https://doi.org/10.1016/j.chembiol.2017.02.006
65. Horton JR, Liu X, Gale M et al (2016) Structural basis for KDM5A histone lysine demethylase
inhibition by diverse compounds. Cell Chem Biol 23:213–221. https://doi.org/10.1016/j.
chembiol.2016.06.006
66. Westaway SM, Preston AGS, Barker MD et al (2016) Cell penetrant inhibitors of the KDM4
and KDM5 families of histone lysine demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one
derivatives. J Med Chem 59:1370–1387. https://doi.org/10.1021/acs.jmedchem.5b01538
67. Bavetsias V, Lanigan RM, Ruda GF et al (2016) 8-substituted pyrido[3,4-d]pyrimidin-4(3H)one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine
demethylase inhibitors. J Med Chem 59:1388. https://doi.org/10.1021/acs.jmedchem.5b01635
252
M. Wright et al.