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

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

doi:10.1021/acs.jmedchem.5b01537.s001

jm5b01537_si_001.pdf (1.54 MB)

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

journal contribution

posted on 2016-01-15, 00:00 authored by Susan M. Westaway, Alex G. S. Preston, Michael D. Barker, Fiona Brown, Jack A. Brown, Matthew Campbell, Chun-wa Chung, Hawa Diallo, Clement Douault, Gerard Drewes, Robert Eagle, Laurie Gordon, Carl Haslam, Thomas G. Hayhow, Philip G. Humphreys, Gerard Joberty, Roy Katso, Laurens Kruidenier, Melanie Leveridge, John Liddle, Julie Mosley, Marcel Muelbaier, Rebecca Randle, Inma Rioja, Anne Rueger, Gail A. Seal, Robert J. Sheppard, Onkar Singh, Joanna Taylor, Pamela Thomas, Douglas Thomson, David M. Wilson, Kevin Lee, Rab K. Prinjha

Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC₅₀ ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC₅₀ = 6–8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC₅₀ = 100–125 nM).