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Targeting lysine specific demethylase 4A (KDM4A) tandem TUDOR domain - A fragment based approach.

  • Upadhyay, Anup K1
  • Judge, Russell A2
  • Li, Leiming2
  • Pithawalla, Ron2
  • Simanis, Justin2
  • Bodelle, Pierre M2
  • Marin, Violeta L2
  • Henry, Rodger F2
  • Petros, Andrew M2
  • Sun, Chaohong2
  • 1 AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA. Electronic address: [email protected]
  • 2 AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA.
Published Article
Bioorganic & medicinal chemistry letters
Publication Date
Apr 19, 2018
DOI: 10.1016/j.bmcl.2018.04.050
PMID: 29691138


The tandem TUDOR domains present in the non-catalytic C-terminal half of the KDM4A, 4B and 4C enzymes play important roles in regulating their chromatin localizations and substrate specificities. They achieve this regulatory role by binding to different tri-methylated lysine residues on histone H3 (H3-K4me3, H3-K23me3) and histone H4 (H4-K20me3) depending upon the specific chromatin environment. In this work, we have used a 2D-NMR based fragment screening approach to identify a novel fragment (1a), which binds to the KDM4A-TUDOR domain and shows modest competition with H3-K4me3 binding in biochemical as well as in vitro cell based assays. A co-crystal structure of KDM4A TUDOR domain in complex with 1a shows that the fragment binds stereo-specifically to the methyl lysine binding pocket forming a network of strong hydrogen bonds and hydrophobic interactions. We anticipate that the fragment 1a can be further developed into a novel allosteric inhibitor of the KDM4 family of enzymes through targeting their C-terminal tandem TUDOR domain.

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