Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 4, Pages 1388-1409Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01635
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Funding
- Cancer Research UK [CUK] [C309/A11566]
- Avon Foundation for Women [02-2013-52]
- AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- NHS
- Biotechnology and Biological Sciences Research Council [BB/L004275/1] Funding Source: researchfish
- Cancer Research UK [18245, 11566] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/L003376/1] Funding Source: researchfish
- BBSRC [BB/L004275/1] Funding Source: UKRI
- EPSRC [EP/L003376/1] Funding Source: UKRI
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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 Fell) 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 H3K9Me(3) and H3K4Me(3) demethylation in a cell-based assay.
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