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.