8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors

DOI: 10.1021/acs.jmedchem.5b01635
PMID: 26741168

Authors: Vassilios Bavetsias (Cancer Research UK Cancer Therapeutics Unit) , Rachel M. Lanigan (Cancer Research UK Cancer Therapeutics Unit) , Gian Filippo Ruda (University of Oxford) , Butrus Atrash (Cancer Research UK Cancer Therapeutics Unit) , Mark G. Mclaughlin (Cancer Research UK Cancer Therapeutics Unit) , Anthony Tumber (University of Oxford) , N. Yi Mok (Cancer Research UK Cancer Therapeutics Unit) , Yann-Vaï Le Bihan (Cancer Research UK Cancer Therapeutics Unit) , Sally Dempster (Cancer Research UK Cancer Therapeutics Unit) , Katherine J. Boxall (Cancer Research UK Cancer Therapeutics Unit) , Fiona Jeganathan (Cancer Research UK Cancer Therapeutics Unit) , Stephanie B. Hatch (University of Oxford) , Pavel Savitsky (University of Oxford) , Velupillai Srikannathasan (Structural Genomic Consortium, Oxford) , Tobias Krojer (Oxford University SGC) , Katherine S. England (University of Oxford) , Jimmy Sejberg (Cancer Research UK Cancer Therapeutics Unit) , Ching Thai (Cancer Research UK Cancer Therapeutics Unit) , Adam Donovan (Cancer Research UK Cancer Therapeutics Unit) , Akos Pal (Cancer Research UK Cancer Therapeutics Unit)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 55 (1)

State: Published (Approved)
Published: January 2016

Abstract: We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.

Journal Keywords: Reaction products; Peptides and proteins; Scaffolds; Inhibitors; Inhibition

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 28/01/2016 13:38

Documents:
acs.jmedchem.5b01635.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)