Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives

  • J Med Chem. 2016 Feb 25;59(4):1370-87. doi: 10.1021/acs.jmedchem.5b01538.
Susan M Westaway  1 Alex G S Preston  1 Michael D Barker  1 Fiona Brown  2 Jack A Brown  1 Matthew Campbell  1 Chun-wa Chung  2 Gerard Drewes  3 Robert Eagle  2 Neil Garton  1 Laurie Gordon  2 Carl Haslam  2 Thomas G Hayhow  1 Philip G Humphreys  1 Gerard Joberty  3 Roy Katso  2 Laurens Kruidenier  1 Melanie Leveridge  2 Michelle Pemberton  2 Inma Rioja  1 Gail A Seal  1 Tracy Shipley  1 Onkar Singh  2 Colin J Suckling  4 Joanna Taylor  2 Pamela Thomas  2 David M Wilson  1 Kevin Lee  1 Rab K Prinjha  1
Affiliations
  • 1. Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
  • 2. Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
  • 3. Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
  • 4. Department of Pure and Applied Chemistry, WestCHEM Research School, University of Strathclyde , Glasgow G1 1XL, U.K.
Abstract

Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays.