In:
Future Medicinal Chemistry, Future Science Ltd, Vol. 8, No. 13 ( 2016-09), p. 1553-1571
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1756-8919
,
1756-8927
Sprache:
Englisch
Verlag:
Future Science Ltd
Publikationsdatum:
2016
SSG:
15,3