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BACKGROUND: Aberrant expression of iron(II)- and 2-oxoglutarate-dependent JumonjiC histone demethylases has been linked to cancer. Potent demethylase inhibitors are drug candidates and biochemical tools to elucidate the functional impact of demethylase inhibition. METHODS & RESULTS: Virtual screening identified a novel lead scaffold against JMJD2A with low-micromolar potency in vitro. Analogs were acquired from commercial sources respectively synthesized in feedback with biological testing. Optimized compounds were transformed into cell-permeable prodrugs. A cocrystal x-ray structure revealed the mode of binding of these compounds as competitive to 2-oxoglutarate and confirmed kinetic experiments. Selectivity studies revealed a preference for JMJD2A and JARID1A over JMJD3. CONCLUSION: Virtual screening and rational structural optimization led to a novel scaffold for highly potent and selective JMJD2A inhibitors.

Original publication




Journal article


Future Med Chem




1553 - 1571


JumonjiC domain, aminopyrimidylpyridines, epigenetics, histone demethylase, metal chelators, prodrugs, virtual screening, Crystallography, X-Ray, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Histone Deacetylase Inhibitors, Humans, Isonicotinic Acids, Jumonji Domain-Containing Histone Demethylases, Models, Molecular, Molecular Structure, Prodrugs, Pyrimidines, Structure-Activity Relationship