5FP3

Cell Penetrant Inhibitors of the Kdm4 and Kdm5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-Pyridine Carboxylate Derivatives.

Westaway, S.M., Preston, A.G.S., Barker, M.D., Brown, F., Brown, J.A., Campbell, M., Chung, C., Diallo, H., Douault, C., Drewes, G., Eagle, R., Gordon, L., Haslam, C., Hayhow, T.G., Humphreys, P.G., Joberty, G., Katso, R., Kruidenier, L., Leveridge, M., Liddle, J., Mosley, J., Muelbaier, M., Randle, R., Rioja, I., Rueger, A., Seal, G.A., Sheppard, R.J., Singh, O., Taylor, J., Thomas, P., Thomson, D., Wilson, D.M., Lee, K., Prinjha, R.K.

(2016) J Med Chem 59: 1357

• PubMed: 26771107 Search on PubMed
• DOI: https://doi.org/10.1021/acs.jmedchem.5b01537
• Primary Citation of Related Structures:  
  5FP3, 5FP4, 5FP8, 5FP9, 5FPA, 5FPB


• PubMed Abstract: 
  

  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).

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Organizational Affiliation: 

Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.