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Tytuł:
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Discovery of a new class of JMJD6 inhibitors and structure-activity relationship study.
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Autorzy:
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Wang T; Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin 300071, PR China.
Zhang R; West China Hospital, Sichuan University, Chengdu 610041, PR China.
Liu Y; West China Hospital, Sichuan University, Chengdu 610041, PR China.
Fang Z; Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin 300071, PR China.
Zhang H; West China Hospital, Sichuan University, Chengdu 610041, PR China.
Fan Y; Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin 300071, PR China.
Yang S; West China Hospital, Sichuan University, Chengdu 610041, PR China.
Xiang R; Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin 300071, PR China. Electronic address: .
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Źródło:
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Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Jul 15; Vol. 44, pp. 128109. Date of Electronic Publication: 2021 May 13.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, c1991-
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MeSH Terms:
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Drug Discovery*
Enzyme Inhibitors/*pharmacology
Jumonji Domain-Containing Histone Demethylases/*antagonists & inhibitors
Pyridines/*pharmacology
Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Humans ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Molecular Structure ; Pyridines/chemical synthesis ; Pyridines/chemistry ; Structure-Activity Relationship
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Contributed Indexing:
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Keywords: JMJD6; Selective inhibitor; Structure-activity relationship; Virtual screening
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Substance Nomenclature:
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0 (Enzyme Inhibitors)
0 (Pyridines)
EC 1.14.11.- (JMJD6 protein, human)
EC 1.14.11.- (Jumonji Domain-Containing Histone Demethylases)
NH9L3PP67S (pyridine)
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Entry Date(s):
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Date Created: 20210515 Date Completed: 20220105 Latest Revision: 20220105
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Update Code:
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20240105
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DOI:
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10.1016/j.bmcl.2021.128109
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PMID:
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33991627
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JmjC domain-containing protein 6 (JMJD6) has been thought as a potential target for various diseases particularly cancer. However, few selective JMJD6 inhibitors have been reported. In this investigation, molecular docking and biological activity evaluation were performed to retrieve new JMJD6 inhibitors, which led to the identification of a hit compound, J2. Further structural optimization and structure-activity relationship (SAR) analysis towards J2 were carried out, which gave a new potent JMJD6 inhibitor, 7p. This compound showed an IC 50 value of 0.681 μM against JMJD6, but displayed no activity against other tested JmjC domain-containing protein family members, indicating good selectivity (>100 fold). Collectively, this investigation offers a selective JMJD6 inhibitor, which could be taken as a lead compound for subsequent drug discovery targeting JMJD6.
(Copyright © 2021. Published by Elsevier Ltd.)
