Identification of the 2‑Benzoxazol-2-yl-phenol Scaffold as New Hit for JMJD3 Inhibition

JMJD3 is a member of the KDM6 subfamily and catalyzes the demethylation of lysine 27 on histone H3 (H3K27). This protein was identified as a useful tool in understanding the role of epigenetics in inflammatory conditions and in cancer as well. Guided by a virtual fragment screening approach, we iden...

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Published in:ACS medicinal chemistry letters 2019-04, Vol.10 (4), p.601-605
Main Authors: Giordano, Assunta, Forte, Giovanni, Terracciano, Stefania, Russo, Alessandra, Sala, Marina, Scala, Maria C, Johansson, Catrine, Oppermann, Udo, Riccio, Raffaele, Bruno, Ines, Di Micco, Simone
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Language:English
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Letter
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Summary:JMJD3 is a member of the KDM6 subfamily and catalyzes the demethylation of lysine 27 on histone H3 (H3K27). This protein was identified as a useful tool in understanding the role of epigenetics in inflammatory conditions and in cancer as well. Guided by a virtual fragment screening approach, we identified the benzoxazole scaffold as a new hit suitable for the development of tighter JMJD3 inhibitors. Compounds were synthesized by a microwave-assisted one-pot reaction under catalyst and solvent-free conditions. Among these, compound 8 presented the highest inhibitory activity (IC50 = 1.22 ± 0.22 μM) in accordance with molecular modeling calculations. Moreover, 8 induced the cycle arrest in S-phase on A375 melanoma cells.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.8b00589