Abstract
Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1.
Keywords:
Epigenetics; Histone lysine demethylase; KDM5; Structure-based design; Tri-methylated H3K4.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Female
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Humans
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors*
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Jumonji Domain-Containing Histone Demethylases / metabolism
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MCF-7 Cells
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Mammary Neoplasms, Experimental / drug therapy
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Mammary Neoplasms, Experimental / pathology
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Models, Molecular
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Molecular Structure
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / metabolism
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Repressor Proteins / antagonists & inhibitors*
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Repressor Proteins / metabolism
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Retinoblastoma-Binding Protein 2 / antagonists & inhibitors*
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Retinoblastoma-Binding Protein 2 / metabolism
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Structure-Activity Relationship
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Nuclear Proteins
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Repressor Proteins
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Jumonji Domain-Containing Histone Demethylases
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KDM5A protein, human
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KDM5B protein, human
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Retinoblastoma-Binding Protein 2