Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives

Journal of Medicinal Chemistry

Volumn 59, Issue 4, 2016, Pages 1357-1369

  Westaway, Susan M ^a   Preston, Alex G S ^a   Barker, Michael D ^a   Brown, Fiona ^a   Brown, Jack A ^a   Campbell, Matthew ^a   Chung, Chun Wa ^a   Diallo, Hawa ^a   Douault, Clement ^a   Drewes, Gerard ^a   Eagle, Robert ^a   Gordon, Laurie ^a   Haslam, Carl ^a   Hayhow, Thomas G ^a   Humphreys, Philip G ^a   Joberty, Gerard ^a   Katso, Roy ^a   Kruidenier, Laurens ^a,d   Leveridge, Melanie ^a   Liddle, John ^a   Mosley, Julie ^a   Muelbaier, Marcel ^a   Randle, Rebecca ^a   Rioja, Inma ^a   Rueger, Anne ^a   Seal, Gail A ^a   Sheppard, Robert J ^a,b   Singh, Onkar ^a   Taylor, Joanna ^a   Thomas, Pamela ^a   Thomson, Douglas ^a   Wilson, David M ^a,b   Lee, Kevin ^a,c   Prinjha, Rab K ^a   more..

^a GLAXOSMITHKLINE   (United Kingdom)

^b ASTRAZENECA   (United Kingdom)

^c Babraham Research Campus   (United Kingdom)

^d TAKEDA PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 AMINO 4 PYRIDINE CARBOXYLATE DERIVATIVE; 3 [(FURAN 2 YLMETHYL)AMINO]PYRIDINE 4 CARBOXYLIC ACID; 3 [[(3 METHYLTHIOPHEN 2 YL)METHYL]AMINO]PYRIDINE 4 CARBOXYLIC ACID; CARBOXYLIC ACID DERIVATIVE; HISTONE DEMETHYLASE; HISTONE LYSINE DEMETHYLASE; OXYGENASE; OXYGENASE INHIBITOR; PROTEIN KDM4; PROTEIN KDM5; PROTEIN KDM6B; UNCLASSIFIED DRUG; ENZYME INHIBITOR; KDM4C PROTEIN, HUMAN; KDM4D PROTEIN, HUMAN; KDM5C PROTEIN, HUMAN; KDM6B PROTEIN, HUMAN; PYRIDINE DERIVATIVE;

ARTICLE; CELL ACTIVITY; CRYSTAL STRUCTURE; DRUG ACTIVITY; IC50; MASS SPECTROMETRY; PHYSICAL CHEMISTRY; RAPIDFIRE MASS SPECTROMETRY; AMINATION; ANTAGONISTS AND INHIBITORS; CELL LINE; CELL MEMBRANE PERMEABILITY; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DESIGN; HUMAN; METABOLISM; X RAY CRYSTALLOGRAPHY;

AMINATION; CELL LINE; CELL MEMBRANE PERMEABILITY; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; ENZYME INHIBITORS; HISTONE DEMETHYLASES; HUMANS; JUMONJI DOMAIN-CONTAINING HISTONE DEMETHYLASES; MODELS, MOLECULAR; PYRIDINES;

EID: 84959421162     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01537     Document Type: Article

References (26)

1. Arrowsmith, C. H.; Bountra, C.; Fish, P. V.; Lee, K.; Schapira, M. Epigenetic protein families: a new frontier for drug discovery Nat. Rev. Drug Discovery 2012, 11, 384-400 10.1038/nrd3674
2. Prinjha, R.; Tarakhovsky, A. Chromatin targeting drugs in cancer and immunity Genes Dev. 2013, 27, 1731-1738 10.1101/gad.221895.113
3. Lora, J. M.; Wilson, D. M.; Lee, K.; Larminie, C. G. C. Epigenetic control of the immune system: histone demethylation as a target for drug discovery Drug Discovery Today: Technol. 2010, 7, e67-e75 10.1016/j.ddtec.2010.10.001
4. Black, J. C.; Van Rechem, C.; Whetstine, J. R. Histone lysine methylation dynamics: Establishment, regulation, and biological impact Mol. Cell 2012, 48, 491-507 10.1016/j.molcel.2012.11.006
5. Copeland, R. A.; Solomon, M. E.; Richon, V. M. Protein methyltransferases as a target class for drug discovery Nat. Rev. Drug Discovery 2009, 8, 724-732 10.1038/nrd2974
6. Lohse, B.; Kristensen, J. L.; Kristensen, L. H.; Agger, K.; Helin, K.; Gajhede, M.; Clausen, R. P. Inhibitors of histone demethylases Bioorg. Med. Chem. 2011, 19, 3625-3636 10.1016/j.bmc.2011.01.046
7. Cloos, P. A.; Christensen, J.; Agger, K.; Maiolica, A.; Rappsilber, J.; Antal, T.; Hansen, K. H.; Helin, K. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3 Nature 2006, 442, 307-311 10.1038/nature04837
8. Hamada, S.; Kim, T. D.; Suzuki, T.; Itoh, Y.; Tsumoto, H.; Nakagawa, H.; Janknecht, R.; Miyata, N. Synthesis and activity of N-oxalylglycine and its derivatives as Jumonji C-domain containing histone lysine demethylase inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 2852-2855 10.1016/j.bmcl.2009.03.098
9. Rose, N. R.; Woon, E. C.; Kingham, G. L.; King, O. N.; Mecinović, J.; Clifton, I. J.; Ng, S. S.; Talib-Hardy, J.; Oppermann, U.; McDonough, M. A.; Schofield, C. J. Selective inhibitors of the JMJD2 histone demethylases: combined nondenaturing mass spectrometric screening and crystallographic approaches J. Med. Chem. 2010, 53, 1810-1818 10.1021/jm901680b
10. Rose, N. R.; Ng, S. S.; Mecinovic, J.; Liénard, B. M. R.; Bello, S. H.; Sun, Z.; McDonough, M. A.; Oppermann, U.; Schofield, C. J. Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases J. Med. Chem. 2008, 51, 7053-7056 10.1021/jm800936s
11. Chang, K. H.; King, O. N.; Tumber, A.; Woon, E. C.; Heightman, T. D.; McDonough, M. A.; Schofield, C. J.; Rose, N. R. Inhibition of histone demethylases by 4-carboxy-2,2′-bipyridyl compounds ChemMedChem 2011, 6 (5) 759-764 10.1002/cmdc.201100026
12. Thalhammer, A.; Mecinovic, J.; Loenarz, C.; Tumber, A.; Rose, N. R.; Heightman, T. D.; Schofield, C. J. Inhibition of the histone demethylase JMJD2E by 3-substituted pyridine 2,4-dicarboxylates Org. Biomol. Chem. 2011, 9, 127-135 10.1039/C0OB00592D
13. Hopkinson, R. J.; Tumber, A.; Yapp, C.; Chowdhury, R.; Aik, W.; Che, K. H.; Li, X. S.; Kristensen, J. B. L.; King, O. N. F.; Chan, M. C.; Yeoh, K. K.; Choi, H.; Walport, L. J.; Thinnes, C. C.; Bush, J. T.; Lejeune, C.; Rydzik, A. M.; Rose, N. R.; Bagg, E. A.; McDonough, M. A.; Krojer, T. J.; Yue, W. W.; Ng, S. S.; Olsen, L.; Brennan, P. E.; Oppermann, U.; Müller, S.; Klose, R. J.; Ratcliffe, P. J.; Schofield, C. J.; Kawamura, A. 5-Carboxy-8-hydroxyquinoline is a broad spectrum 2-oxoglutarate oxygenase inhibitor which causes iron translocation Chem. Sci. 2013, 4, 3110-3117 10.1039/c3sc51122g
14. 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. Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases J. Med. Chem. 2012, 55, 6639-6643 10.1021/jm300677j
15. 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. A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases J. Am. Chem. Soc. 2011, 133, 9451-9456 10.1021/ja201597b
16. 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. Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of Jumonji domain-containing protein 2 histone demethylase inhibitors J. Med. Chem. 2010, 53, 5629-5638 10.1021/jm1003655
17. Sekirnik, R.; Rose, N. R.; Thalhammer, A.; Seden, P. T.; Mecinovic, J.; Schofield, C. J. Inhibition of the histone lysine demethylase JMJD2A by ejection of structural Zn(II) Chem. Commun. 2009, 6376-6378 10.1039/b916357c
18. Rai, G.; Kawamura, A.; Tumber, A.; Liang, Y.; Vogel, J. L.; Arbuckle, J. H.; Rose, N. R.; Dexheimer, T. S.; Foley, T. L.; King, O. N.; Quinn, A.; Mott, B. T.; Schofield, C. J.; Oppermann, U.; Jadhav, A.; Simeonov, A.; Kristie, T. M.; Maloney, D. J. Discovery of ML324, a JMJD2 demethylase inhibitor with demonstrated antiviral activity. Probe Reports from the NIH Molecular Libraries Program; National Center for Biotechnology Information (US): Bethesda, MD, 2010-2012.
19. 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. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response Nature 2012, 488, 404-408 10.1038/nature11262
20. Hutchinson, S. E.; Leveridge, M. V.; Heathcote, M.; Francis, P.; Williams, L.; Gee, M.; Munoz-Muriedas, J.; Leavens, B.; Shillings, A.; Jones, E.; Homes, P.; Baddeley, S.; Chung, C. W.; Bridges, A.; Argyrou, A. Enabling lead discovery for histone lysine demethylases by high-throughput RapidFire mass spectrometry J. Biomol. Screening 2012, 17, 39-48 10.1177/1087057111416660
21. Wong, B. W.; Kuchnio, A.; Bruning, U.; Carmeliet, P. Emerging novel functions of oxygen-sensing prolyl hydroxylase domain enzymes Trends Biochem. Sci. 2013, 38, 3-11 10.1016/j.tibs.2012.10.004
22. Diaz, R.; Luengo-Arratta, S. A.; Seixas, J. D.; Amata, E.; Devine, W.; Cordon-Obras, C.; Rojas-Barros, D. I.; Jimenez, E.; Ortega, F.; Crouch, S. Identification and characterization of hundreds of potent and selective inhibitors of Trypanosoma brucei growth from a kinase-targeted library screening campaign PLoS Neglected Trop. Dis. 2014, 8, e3253 10.1371/journal.pntd.0003253
23. Compounds 12-15, 17-34, 36-39, and 41-43 have been disclosed in the following patent application: Barker, M. D.; Campbell, M.; Diallo, H.; Douault, C.; Humphreys, P.; Liddle, J.; Sheppard, R. J.; Thomas, P. J.; Wilson, D. M. Demethylase enzymes inhibitors. PCT Int. Appl. WO2013143597, 2013.
24. Compound 37 has also been disclosed in the following patent application: Chen, Y. K.; Kanouni, T.; Nie, Z.; Stafford, J. A.; Veal, J. M.; Wallace, M. B. Histone demethylase inhibitors. PCT Int. Appl. WO2014100818, 2014.
25. Joberty, G.; Boesche, M.; Brown, J. A.; Eberhard, D.; Garton, N. S.; Muelbaier, M.; Ramsden, N.; Reader, V.; Rueger, A.; Sheppard, R. J.; Westaway, S. M.; Bantscheff, M.; Lee, K.; Wilson, D. M.; Prinjha, R. K.; Drewes, G. Interrogating the druggability of the 2-oxoglutarate-dependent dioxygenase target class by chemical proteomics. Unpublished results, 2015.
26. Westaway, S. M.; Preston, A. G. S.; Barker, M. D.; Brown, F.; Brown, J. A.; Campbell, M.; Chung, C.-W.; Drewes, G.; Eagle, R.; Garton, N.; Gordon, L.; Haslam, C.; Hayhow, T. G.; Humphreys, P. G.; Joberty, G.; Katso, R.; Kruidenier, L.; Leveridge, M.; Pemberton, M.; Rioja, I.; Seal, G. A.; Shipley, T.; Singh, O.; Suckling, C. J.; Taylor, J.; Thomas, P.; Wilson, D. M.; Lee, K.; Prinjha, R. K. 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. 2016, 10.1021/acs.jmedchem.5b01538.