Advertisement

Targeting Histone Lysine Demethylases by Truncating the Histone 3 Tail to Obtain Selective Substrate-Based Inhibitors

Authors

  • Brian Lohse,

    1. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    Search for more papers by this author
  • Anders L. Nielsen,

    1. Biopharmaceutical Chemistry, Novo Nordisk A/S, 2760 Måløv (Denmark)
    Search for more papers by this author
  • Jan B. L. Kristensen,

    1. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    Search for more papers by this author
  • Charlotte Helgstrand,

    1. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    Search for more papers by this author
  • Paul A. C. Cloos,

    1. Research & Innovation Centre, 2200 Copenhagen N (Denmark)
    Search for more papers by this author
  • Lars Olsen,

    1. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    Search for more papers by this author
  • Michael Gajhede,

    1. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    Search for more papers by this author
  • Rasmus P. Clausen,

    Corresponding author
    1. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    • Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    Search for more papers by this author
  • Jesper L. Kristensen

    Corresponding author
    1. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    • Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    Search for more papers by this author

  • The University of Copenhagen Program of Excellence, the Danish National Research Foundation, the Danish Medical Research Council, and the Danish Cancer Society are gratefully acknowledged for financial support. We thank Novo Nordisk A/S for supplying selected substrates and access to MALDI-TOF MS. We also thank Prof. Kristian Helin for supplying histone tails, protein expression vectors, and insect cells, and for valuable discussions.

Abstract

original image

How low can you go? The natural substrate for the epigenetic regulators PHF8, JmjD2A, and JmjD2C (lysine demethylases), a peptide consisting of 39 amino acid residues, can be truncated to 14, 8, and 4 amino acids, respectively, while maintaining catalytic activity (see picture). Inhibitors were prepared by attaching small molecules to the truncated substrates. Selective inhibition of JmjD2C over JmjD2A and PHF8 was possible.

Ancillary