Inhibition of JMJD6 by 2‐Oxoglutarate Mimics. (16th November 2021)

• Record Type: Journal Article
• Authors: Islam, Md. Sailful; Thinnes, Cyrille C.; Holt‐Martyn, James P.; Chowdhury, Rasheduzzaman; McDonough, Michael A.; Schofield, Christopher J.
• Is Part Of: ChemMedChem. Volume 17:Number 1(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-11-16
• Subjects: JMJD6 -- JmjC hydroxylase / demethylase -- prostate cancer -- 2-oxogluturate / α-ketoglutarate -- oxygenase inhibition -- epigenetics -- isocitrate dehydrogenase -- 2-hydroxygluturate -- hypoxia -- HIF -- PHD inhibitors.; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100398
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Studies on the inhibition of the human 2‐oxoglutarate dependent oxygenase JMJD6, which is a cancer target, by 2‐oxoglutarate mimics / competitors, including human drugs, drug candidates, and metabolites relevant to cancer are described. JMJD6 assays employed NMR to monitor inhibitor binding and use of mass spectrometry to monitor JMJD6‐catalysed lysine hydroxylation. Notably, some clinically applied prolyl hydroxylase inhibitors also inhibit JMJD6. The results will help enable the development of inhibitors selective for human oxygenases, including JMJD6. Abstract : Selective for human oxygenases : 2‐Oxoglutarate‐dependent oxygenases such as JMJD6 are targets for treatment of diseases including cancer and anemia. NMR and MS assays on JMJD6, a prostate cancer target, identify 2‐oxoglutarate competitors, including human drugs and drug candidates, as JMJD6 inhibitors. Notably, some clinically applied HIF prolyl hydroxylase inhibitors also inhibit JMJD6. The results will help enable the development of selective inhibitors for human oxygenases, including JMJD6.