Journal
FUTURE MEDICINAL CHEMISTRY
Volume 8, Issue 13, Pages 1553-1571Publisher
FUTURE SCI LTD
DOI: 10.4155/fmc.15.188
Keywords
aminopyrimidylpyridines; epigenetics; histone demethylase; JumonjiC domain; metal chelators; prodrugs; virtual screening
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Funding
- Collaborative Research Center CRC 992 MEDEP 'Medical Epigenetics' [A04, B01]
- European Research Council (ERC) [322844]
- Deutsche Forschungsgemeinschaft [CRC 850, CRC 746, Schu688/12-1]
- COST action [CM1406]
- Medical Research Council UK [MR/K018779/1]
- Studienstiftung des deutschen Volkes
- MRC [MR/K018779/1] Funding Source: UKRI
- Medical Research Council [MR/K018779/1] Funding Source: researchfish
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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.
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