Design, synthesis, and biological evaluation of indolin-2-one derivatives as novel cyclin-dependent protein kinase 8 (CDK8) inhibitors.

Humans Cyclin-Dependent Kinases / metabolism Cyclin-Dependent Kinase 8 Indoles / pharmacology Transforming Growth Factor beta1 / metabolism Phosphorylation Signal Transduction Fibrosis Idiopathic Pulmonary Fibrosis / drug therapy Epithelial-Mesenchymal Transition Protein Kinase Inhibitors / pharmacology
Cyclin-dependent protein kinase 8 (CDK8) Idiopathic pulmonary fibrosis (IPF) Indolin-2-one Kinase inhibitor Lead optimization

Journal

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
ISSN: 1950-6007
Titre abrégé: Biomed Pharmacother
Pays: France
ID NLM: 8213295

Informations de publication

Date de publication:
Mar 2023
Historique:
received: 22 11 2022
revised: 10 01 2023
accepted: 14 01 2023
pubmed: 29 1 2023
medline: 8 2 2023
entrez: 28 1 2023
Statut: ppublish

Résumé

Cyclin-dependent protein kinase 8 (CDK8) plays important roles in regulating fibrotic growth factors and inflammatory signaling pathways. Long-term chronic inflammation of the lungs can lead to idiopathic pulmonary fibrosis (IPF). Abnormal alveolar epithelial regeneration leads to the release of various fibrotic growth factors and the activation of inflammatory cells. CDK8 regulates profibrotic cytokines broadly implicated in the pathogenesis of fibrosis. Therefore, inhibition of CDK8 is considered a promising strategy for treating IPF. Here, CDK8 inhibitors were designed and optimized using a fragment-based drug design strategy. Testing results revealed that 71% of the synthesized compounds inhibited CDK8 activity better than the original compound E966-0530. Of these compounds, compound 4k exhibited the strongest CDK8 enzyme-inhibiting activity (IC

Identifiants

DOI: 10.1016/j.biopha.2023.114258 PMID: 36708700
pubmed: 36708700
pii: S0753-3322(23)00046-X
doi: 10.1016/j.biopha.2023.114258
pii:
doi:

Substances chimiques

indolin-2-one 0
Cyclin-Dependent Kinases EC 2.7.11.22
Cyclin-Dependent Kinase 8 EC 2.7.11.22
Indoles 0
Transforming Growth Factor beta1 0
Protein Kinase Inhibitors 0
CDK8 protein, human EC 2.7.11.22

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

114258

Informations de copyright

Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest statement 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.

Auteurs

Jui-Yi Hsu (JY)

Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan; Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Kai-Cheng Hsu (KC)

Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

Ching Sun (C)

School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.

Ching-Hsuan Chou (CH)

School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.

Tony Eight Lin (TE)

Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.

Tzu-Ying Sung (TY)

Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan.

Hui-Ju Tseng (HJ)

Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States.

Shih-Chung Yen (SC)

Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, People's Republic of China.

Chia-Ron Yang (CR)

School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: cryang@ntu.edu.tw.

Wei-Jan Huang (WJ)

Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; School of Pharmacy, Taipei Medical University, Taipei, Taiwan. Electronic address: wjhuang@tmu.edu.tw.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Design, synthesis, and biological evaluation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Kinases cyclines-dépendantes › Design, synthesis, and biological evaluation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Complexe médiateur › Cyclin-Dependent Kinase 8 › Design, synthesis, and biological evaluation...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Indoles › Design, synthesis, and biological evaluation...
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questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Design, synthesis, and biological evaluation...