4‐Biphenylalanine‐ and 3‐Phenyltyrosine‐Derived Hydroxamic Acids as Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A |
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| Authors: | Dr Ludovica Morera Dr Martin Roatsch Michael C D Fürst Dr Inga Hoffmann Dr Johanna Senger Mirjam Hau Dr Henriette Franz Prof Dr Roland Schüle Prof Dr Markus R Heinrich Prof Dr Manfred Jung |
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| Affiliation: | 1. Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, Germany;2. Department of Chemistry and Pharmacy, Friedrich Alexander University ErlangenNuremberg, Germany;3. Central Clinical Research, University Medical Center Freiburg, Germany;4. Institute of Anatomy and Cell Biology, Albert Ludwigs University Freiburg, Freiburg im Breisgau, Germany |
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| Abstract: | Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate‐based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm . Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low‐micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell‐permeable derivatives clearly showed a demethylase‐inhibition‐dependent antiproliferative effect against HL‐60 human promyelocytic leukemia cells. |
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| Keywords: | epigenetics histone demethylase inhibitors medicinal chemistry radical reactions |
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