ArticleJournal of medicinal chemistry2016
8-Substituted Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives As Potent, Cell Permeable, KDM4 (JMJD2) and KDM5 (JARID1) Histone Lysine Demethylase Inhibitors.
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Article in Journal of medicinal chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48 citing papers in PubMed.
- Integrated structure-based and fragment-guided design of isonicotinic acid derivatives as potential KDM4A inhibitors: an in silico study.Journal of computer-aided molecular design · 2026Article
- An Intrinsically Disordered Region of Histone Demethylase KDM5A Activates Catalysis Through Interactions With the Nucleosomal Acidic Patch and DNA.Journal of molecular biology · 2025Article
- An intrinsically disordered region of histone demethylase KDM5A activates catalysis through interactions with the nucleosomal acidic patch and DNA.bioRxiv : the preprint server for biology · 2025Article
- Targeting N-Methyl-lysine Histone Demethylase KDM4 in Cancer: Natural Products Inhibitors as a Driving Force for Epigenetic Drug Discovery.ChemMedChem · 2025Review
- Exploring the Potential of Pyridine Carboxylic Acid Isomers to Discover New Enzyme Inhibitors.Drug design, development and therapy · 2025Review
- Pharmacological agents targeting drug-tolerant persister cells in cancer.Pharmacological research · 2024Review
- The emerging roles of lysine-specific demethylase 4A in cancer: Implications in tumorigenesis and therapeutic opportunities.Genes & diseases · 2024Review
- Exploration of Pyrido[3,4-Molecules (Basel, Switzerland) · 2023Article
- Impact of Hydrophobic Chains in Five-Coordinate Glucoconjugate Pt(II) Anticancer Agents.International journal of molecular sciences · 2023Article
- KDM4 Demethylases: Structure, Function, and Inhibitors.Advances in experimental medicine and biology · 2023Article
- Recent Advances with KDM4 Inhibitors and Potential Applications.Journal of medicinal chemistry · 2022Review
- Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively targets castration-resistant prostate cancer.Journal of biomedical science · 2022Article
- Histone Methylases and Demethylases Regulating Antagonistic Methyl Marks: Changes Occurring in Cancer.Cells · 2022Review
- Computational Prediction of the Binding Pose of Metal-Binding Pharmacophores.ACS medicinal chemistry letters · 2022Article
- Transcriptomic and Drug Discovery Analyses Reveal Natural Compounds Targeting the KDM4 Subfamily as Promising Adjuvant Treatments in Cancer.Frontiers in genetics · 2022Article
- JARID1-targeted histone H3 demethylase inhibitors exhibit anti-proliferative activity and overcome cisplatin resistance in canine oral melanoma cell lines.Veterinary and comparative oncology · 2021Article
- Competitive SPR using an intracellular anti-LMO2 antibody identifies novel LMO2-interacting compounds.Journal of immunological methods · 2021Article
- A KDM4A-PAF1-mediated epigenomic network is essential for acute myeloid leukemia cell self-renewal and survival.Cell death & disease · 2021Article
- Article
- A cell-based screening method using an intracellular antibody for discovering small molecules targeting the translocation protein LMO2.Science advances · 2021Article
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Authors and funding
43 authors.
Vassilios BavetsiasCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Rachel M LaniganCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Gian Filippo RudaStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Butrus AtrashCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Mark G McLaughlinCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Anthony TumberStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
N Yi MokCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Yann-Vaï Le BihanCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Sally DempsterCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Katherine J BoxallCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Fiona JeganathanCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Stephanie B HatchStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Pavel SavitskyStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Srikannathasan VelupillaiStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Tobias KrojerStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Katherine S EnglandStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Jimmy SejbergCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Ching ThaiCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Adam DonovanCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Akos PalCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Giuseppe ScozzafavaStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
James M BennettStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Akane KawamuraChemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
Catrine JohanssonStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Aleksandra SzykowskaStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Carina GileadiStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Nicola A Burgess-BrownStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Frank von DelftStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Udo OppermannStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Zoe WaltersDivisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research , London SM2 5NG, U.K.
Janet ShipleyDivisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research , London SM2 5NG, U.K.
Florence I RaynaudCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Susan M WestawayEpinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
Rab K PrinjhaEpinova Discovery Performance Unit, Medicines Research Centre, GlaxoSmithKline R&D , Stevenage SG1 2NY, U.K.
Oleg FedorovStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Rosemary BurkeCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Christopher J SchofieldChemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
Isaac M WestwoodCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Chas BountraStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Susanne MüllerStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Rob L M van MontfortCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Paul E BrennanStructural Genomics Consortium (SGC), University of Oxford , ORCRB Roosevelt Drive, Oxford OX3 7DQ, U.K.
Julian BlaggCancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, London SM2 5NG, U.K.
Funding
Cancer Research UK 11566Cancer Research UK 18245Cancer Research UK C309/A11566Wellcome Trust 092809/Z/10/ZWellcome Trust 106169
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.
Indexed as
Caco-2 CellsCell Membrane PermeabilityEnzyme InhibitorsHumansJumonji Domain-Containing Histone DemethylasesNuclear ProteinsPyrimidinonesRepressor ProteinsEnzyme InhibitorsJumonji Domain-Containing Histone DemethylasesKDM4A protein, humanKDM4D protein, humanKDM5B protein, humanNuclear ProteinsPyrimidinonesRepressor Proteins
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