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

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 10; pp. 1708 - 1713
• Main Authors: Upadhyay, Anup K., Judge, Russell A., Li, Leiming, Pithawalla, Ron, Simanis, Justin, Bodelle, Pierre M., Marin, Violeta L., Henry, Rodger F., Petros, Andrew M., Sun, Chaohong
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2018; Elsevier
• Subjects: 2D-NMR based fragment screening; Dose-Response Relationship, Drug; Fragment based drug discovery; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Jumonji Domain-Containing Histone Demethylases - chemistry; Jumonji Domain-Containing Histone Demethylases - metabolism; KDM4A tandem TUDOR domain; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Structure-Activity Relationship; Tudor Domain; CSP; NMR; JHDM; ITC; Fragment based drug discovery; KDM4A tandem TUDOR domain; 2D-NMR based fragment screening; JmjC
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.04.050

[Display omitted]
•Identified fragment 1a that competes with H3K4me3 binding in KDM4A TUDOR domain.•X-ray structure of KDM4A TUDOR domain in complex with 1a is presented.•Specificity of 1a towards TUDOR domains from other proteins is presented.
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.