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Tytuł:
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Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation.
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Autorzy:
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Yu M; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Teo T; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Yang Y; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Li M; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Long Y; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Philip S; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Noll B; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Heinemann GK; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Diab S; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Eldi P; Experimental Therapeutics, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Mekonnen L; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Anshabo AT; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Rahaman MH; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Milne R; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Hayball JD; Experimental Therapeutics, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia.
Wang S; Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia. Electronic address: .
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Źródło:
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European journal of medicinal chemistry [Eur J Med Chem] 2021 Mar 15; Vol. 214, pp. 113248. Date of Electronic Publication: 2021 Feb 03.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
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MeSH Terms:
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Drug Design*
Antineoplastic Agents/*pharmacology
Cyclin-Dependent Kinase 8/*antagonists & inhibitors
Protein Kinase Inhibitors/*pharmacology
Pyridines/*pharmacology
Administration, Oral ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/chemistry ; Biological Availability ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cyclin-Dependent Kinase 8/metabolism ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; Female ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Structure ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/chemistry ; Pyridines/administration & dosage ; Pyridines/chemistry ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship
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Contributed Indexing:
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Keywords: CDK8 inhibitor; Drug-like properties; Pharmacokinetics; Structure-activity relationship; Toxicity
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Substance Nomenclature:
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0 (Antineoplastic Agents)
0 (Protein Kinase Inhibitors)
0 (Pyridines)
EC 2.7.11.22 (CDK8 protein, human)
EC 2.7.11.22 (Cyclin-Dependent Kinase 8)
NH9L3PP67S (pyridine)
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Entry Date(s):
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Date Created: 20210211 Date Completed: 20210430 Latest Revision: 20210430
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Update Code:
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20240104
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DOI:
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10.1016/j.ejmech.2021.113248
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PMID:
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33571827
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CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in supressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein we detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chemistry optimisation gave rise to 38 (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukaemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicology was observed in the mice treated with 38. These results warrant further pre-clinical studies of 38 as an anti-cancer agent.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
