Article

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

Susan M. Westaway^*^†, Alex G. S. Preston^*^†, Michael D. Barker^†, Fiona Brown^‡, Jack A. Brown^†, Matthew Campbell^†, Chun-wa Chung^‡, Gerard Drewes^§, Robert Eagle^‡, Neil Garton^†, Laurie Gordon^‡, Carl Haslam^‡, Thomas G. Hayhow^†, Philip G. Humphreys^†, Gerard Joberty^§, Roy Katso^‡, Laurens Kruidenier^†, Melanie Leveridge^‡, Michelle Pemberton^‡, Inma Rioja^†, Gail A. Seal^†, Tracy Shipley^†, Onkar Singh^‡, Colin J. Suckling^∥, Joanna Taylor^‡, Pamela Thomas^‡, David M. Wilson^†, Kevin Lee^†, and Rab K. Prinjha^†

^† Epinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage SG1 2NY, U.K.

^‡ Platform Technology and Sciences, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage SG1 2NY, U.K.

^§ Cellzome GmbH, a GSK Company, Meyerhofstrasse 1, 69117 Heidelberg, Germany

^∥ Department of Pure and Applied Chemistry, WestCHEM Research School, University of Strathclyde, Glasgow G1 1XL, U.K.

J. Med. Chem., 2016, 59 (4), pp 1370–1387

DOI: 10.1021/acs.jmedchem.5b01538

Publication Date (Web): January 15, 2016

*S.M.W.: e-mail, sue.m.westaway@gsk.com; telephone, +44 (0)1438763469., *A.G.S.P.: e-mail, alex.gs.preston@gsk.com; telephone, +44 (0)1438790152.

This article is part of the

Epigenetics

special issue.

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.

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01538.

LCMS spectra and selectivity profiling data for 31, 32, 36, 39, and 41; KDM4C RFMS assay data for compounds 47–49; X-ray crystallography methods and data for compounds 3, 4, and 33 bound to KDM4D (PDF)
Molecular formula strings (CSV)

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Dr.T の薬学コラム

2017年3月14日火曜日

Bicyclic KDM Modulators 2016

Article

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

Abstract

Supporting Information

PDF

Interrogating the Druggability of the 2-Oxoglutarate-Dependent Dioxygenase Target Class by Chemical Proteomics

Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives

8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors

Assessing histone demethylase inhibitors in cells: lessons learned

Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells

Pyrido[3,4- d ]pyrimidin-4(3 H )-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution

Design and evaluation of 1,7-naphthyridones as novel KDM5 inhibitors

Identification of potent, selective KDM5 inhibitors

Advances and challenges in understanding histone demethylase biology

Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds

Structural analysis of human KDM5B guides histone demethylase inhibitor development

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