2. Academic Validation
  3. Identification of pyrazole scaffold inhibitors targeting cyclin-dependent kinase 8 for potential use in pulmonary fibrosis

Identification of pyrazole scaffold inhibitors targeting cyclin-dependent kinase 8 for potential use in pulmonary fibrosis

  • Biochem Pharmacol. 2025 Jul:237:116959. doi: 10.1016/j.bcp.2025.116959.
Tony Eight Lin 1,  Kai-Cheng Hsu 2,  Ching-Hsuan Chou 3,  En-Yun Tsai 3,  Yi-Wen Wu 4,  Tzu-Ying Sung 4,  Jui-Yi Hsu 1,  Jui-Hua Hsieh 5,  Shih-Chung Yen 6,  Yu-Wei Chang 7,  Shiow-Lin Pan 8,  Wei-Jan Huang 9,  Chia-Ron Yang 10
Affiliations

Affiliations

  • 1 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.
  • 2 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; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 3 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 4 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 5 Division of Translational Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC, USA.
  • 6 Warshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, China.
  • 7 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung Medical Center, Keelung, Taiwan.
  • 8 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; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 9 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.
  • 10 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: cryang@ntu.edu.tw.
PMID: 40280247 DOI: 10.1016/j.bcp.2025.116959
Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a disease that includes inflammation and scarring of the lung tissues. Cyclin-dependent kinase 8 (CDK8) is a target of interest due to its role in inflammatory pathways. CDK8 can also modulate the TGF-β/Smad signaling associated with IPF. Herein, a structure-based virtual screening (SBVS) campaign led to the identification of three CDK8 inhibitors. Testing of candidate inhibitors in protein and cellular assays confirmed CDK8 inhibition, with the most potent inhibitor producing an IC50 value of 398.8 nM. Computational analysis identified pharmacological interactions that lead to CDK8 inhibition. No significant cytotoxicity was observed when the inhibitor was treated in vitro. Further results showed that the inhibitor can disrupt proteins associated with the epithelial-mesenchymal transition (EMT) and reduce cell migration. Additionally, the inhibitor can disrupt the TGF- β1/Smad signaling axis in the nucleus, potentially impacting the transcription of IPF related protein expression, when treated in cells at 5 µM. Comparisons to structures of known CDK8 inhibitors showed the identified inhibitor to be structurally novel. When tested against a panel of kinases at 1 µM, the most potent inhibitor demonstrated a favorable CDK8 selectivity profile. The identification of the CDK8 inhibitors in this study can be used in future drug design studies and as CDK8 probes to explore alternative therapeutics for IPF.

Keywords

Cyclin-dependent kinase 8; Inflammation; Pulmonary fibrosis; Small-molecule inhibitor; Structure-based virtual screening.

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