title: Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives.
abstract: Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2-ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2-yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 ≤ 100 nM, in KDM4 family biochemical (RFMS) assays with ≥ 50-fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 μM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM).
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Westaway
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Alex G S
authors.initials: AG
authors.lastname: Preston
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Barker
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Fiona
authors.initials: F
authors.lastname: Brown
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Hawa
authors.initials: H
authors.lastname: Diallo
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Clement
authors.initials: C
authors.lastname: Douault
authors.affiliation: Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Robert
authors.initials: R
authors.lastname: Eagle
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Laurie
authors.initials: L
authors.lastname: Gordon
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Carl
authors.initials: C
authors.lastname: Haslam
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hayhow
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Humphreys
authors.affiliation: Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Joberty
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Roy
authors.initials: R
authors.lastname: Katso
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Laurens
authors.initials: L
authors.lastname: Kruidenier
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Melanie
authors.initials: M
authors.lastname: Leveridge
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: John
authors.initials: J
authors.lastname: Liddle
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Julie
authors.initials: J
authors.lastname: Mosley
authors.affiliation: Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Muelbaier
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Randle
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Inma
authors.initials: I
authors.lastname: Rioja
authors.affiliation: Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Rueger
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Gail A
authors.initials: GA
authors.lastname: Seal
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sheppard
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Onkar
authors.initials: O
authors.lastname: Singh
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Joanna
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Platform Technology and Science, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Pamela
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Cellzome GmbH, a GSK Company , Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors.forename: Douglas
authors.initials: D
authors.lastname: Thomson
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
mesh_terms: D000586:Amination; D002460:Cell Line; D002463:Cell Membrane Permeability; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; C413655:KDM4C protein, human; D011725:Pyridines; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C521694:KDM4D protein, human; C086877:KDM5C protein, human; C524220:KDM6B protein, human