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

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

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.
PMID: 26771203 DOI: 10.1021/acs.jmedchem.5b01538
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.

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