Inhibition of Histone Demethylases by 4-Carboxy-2,2′-Bipyridyl Compounds

• Published in: ChemMedChem Vol. 6; no. 5; pp. 759 - 764
• Main Authors: Chang, Kai-Hsuan, King, Oliver N. F., Tumber, Anthony, Woon, Esther C. Y., Heightman, Tom D., McDonough, Michael A., Schofield, Christopher J., Rose, Nathan R.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 02.05.2011; WILEY‐VCH Verlag
• Subjects: 2,2'-Dipyridyl - chemical synthesis; 2,2'-Dipyridyl - chemistry; 2,2'-Dipyridyl - pharmacology; 2-oxoglutarate; Binding Sites; bipyridyl derivatives; Computer Simulation; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; epigenetics; histone demethylases; Humans; inhibitors; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors; Jumonji Domain-Containing Histone Demethylases - metabolism; Ketoglutaric Acids - chemistry; Protein Structure, Tertiary; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201100026

Exploiting epigenetics: 2‐Oxoglutarate (2OG)‐dependent histone lysine demethylases, such as JMJD2E, are potential therapeutic targets in a range of diseases. Through structure–activity relationship studies and analyses, we identified a potent 4‐carboxy‐2,2′‐bipyridyl compound, which inhibits JMJD2E with an IC50 value of 110 nM, representing a 66‐fold improvement over the lead compound. These bipyridyl derivatives bind in the 2‐oxoglutarate binding site.