2. Academic Validation
  3. The study of a novel CDK8 inhibitor E966-0530-45418 that inhibits prostate cancer metastasis in vitro and in vivo

The study of a novel CDK8 inhibitor E966-0530-45418 that inhibits prostate cancer metastasis in vitro and in vivo

  • Biomed Pharmacother. 2023 Jun:162:114667. doi: 10.1016/j.biopha.2023.114667.
Tai-Yuan Ho 1,  Ting-Yi Sung 1,  Shiow-Lin Pan 2,  Wei-Jan Huang 3,  Kai-Cheng Hsu 4,  Jui-Yi Hsu 5,  Tony Eight Lin 6,  Chia-Ming Hsu 6,  Chia-Ron Yang 7
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Medicine, National Taiwan 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 in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, 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 for Drug Discovery, Taipei Medical University, Taipei, Taiwan.
  • 3 School of Pharmacy, Taipei Medical University, Taipei, Taiwan; Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 4 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.
  • 5 Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
  • 6 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 7 School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: cryang@ntu.edu.tw.
PMID: 37037092 DOI: 10.1016/j.biopha.2023.114667
Abstract

Prostate Cancer is a prevalent malignancy among men globally, and androgen deprivation therapy is the conventional first-line treatment for metastatic prostate Cancer. While androgen deprivation therapy is efficacious in castration-sensitive prostate Cancer, it remains less effective in castration-resistant cases. Transcriptional dysregulation is a well-established hallmark of Cancer, and targeting proteins involved in transcriptional regulation, such as cyclin-dependent kinase 8 (CDK8), has become an attractive therapeutic strategy. CDK8, a nuclear serine-threonine kinase, is a key component of the mediator complex and plays a critical role in transcriptional regulation. Recent studies have highlighted the promising role of CDK8 as a target in the treatment of metastatic prostate Cancer. Our study assessed the efficacy of a novel CDK8 Inhibitor, E966-0530-45418, which exhibited potent CDK8 inhibition (IC50 of 129 nM) and high CDK8 selectivity. Treatment with E966-0530-45418 significantly inhibited prostate Cancer cell migration and epithelial-to-mesenchymal transition (EMT) at both the RNA and protein levels. Further mechanistic analysis indicated that E966-0530-45418 suppresses prostate Cancer metastasis by decreasing CDK8 activity and inhibiting TGF-β1-mediated SMAD3/RNA polymerase II linker phosphorylation and Akt/GSK3β/β-catenin signaling. The results in animal model also showed that E966-0530-45418 exhibited anti-metastatic properties in vivo. Our study demonstrated that E966-0530-45418 has great therapeutic potential in the treatment of metastatic prostate Cancer.

Keywords

Cyclin-dependent kinase 8; Epithelial-to-mesenchymal transition; Mediator complex; Metastasis; Prostate cancer.

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