2. Academic Validation
  3. Identification of a Potent CDK8 Inhibitor Using Structure-Based Virtual Screening

Identification of a Potent CDK8 Inhibitor Using Structure-Based Virtual Screening

  • J Chem Inf Model. 2025 Jan 13;65(1):378-389. doi: 10.1021/acs.jcim.4c02011.
Tony Eight Lin 1 2,  Ching-Hsuan Chou 3,  Yi-Wen Wu 1,  Tzu-Ying Sung 1,  Jui-Yi Hsu 1 2,  Shih-Chung Yen 4,  Jui-Hua Hsieh 5,  Yu-Wei Chang 2 6,  Shiow-Lin Pan 1 2 7 8,  Wei-Jan Huang 7 9,  Kai-Cheng Hsu 1 2 7 8 10,  Chia-Ron Yang 3
Affiliations

Affiliations

  • 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
  • 2 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
  • 3 School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
  • 4 Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong 518172, People's Republic of China.
  • 5 Division of Translational Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, North Carolina 27709-2233, United States.
  • 6 Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung Medical Center, Keelung 20401,Taiwan.
  • 7 Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
  • 8 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031,Taiwan.
  • 9 School of Pharmacy, Taipei Medical University, Taipei 10051, Taiwan.
  • 10 Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696,Taiwan.
PMID: 39740163 DOI: 10.1021/acs.jcim.4c02011
Abstract

Pulmonary fibrosis is excessive scarring of the lung tissues. Transforming growth factor-beta (TGF-β) has been implicated in pulmonary fibrosis due to its ability to induce the epithelial-to-mesenchymal transition (EMT) and promote epithelial cell migration. Cyclin-dependent kinase 8 (CDK8) can mediate the TGF-β signaling pathways and could function as an alternative therapeutic target for treating pulmonary fibrosis. Here, we performed a structure-based virtual screening campaign to identify CDK8 inhibitors from a library of 1.6 million compounds. The screening process ended with the identification of a novel CDK8 Inhibitor, P162-0948 (IC50: 50.4 nM). An interaction analysis highlighted important CDK8-ligand interactions that support its binding and inhibitory activity. Testing against a panel of 60 different kinases demonstrated P162-0948 selectivity toward CDK8. Crucially, the inhibitor was found to be structurally novel when compared to known CDK8 inhibitors. Testing in A549 human alveolar epithelial cell lines showed that the P162-0948 can reduce cell migration and protein expression of EMT-related proteins. When P162-0948 was treated in cells at 5 μM, phosphorylation of Smad in the nucleus was reduced, which suggests disruption of the TGF-β/Smad signaling pathway. The identification of P162-0948 shows that it is not only potent, but its structural novelty can inform future design studies for potential therapeutics targeting pulmonary fibrosis.

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