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

Tai-Yuan Ho; Ting-Yi Sung; Shiow-Lin Pan; Wei-Jan Huang; Kai-Cheng Hsu; Jui-Yi Hsu; Tony Eight Lin; Chia-Ming Hsu; Chia-Ron Yang

doi:10.1016/j.biopha.2023.114667

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. Epub 2023 Apr 8.

Authors

Tai-Yuan Ho¹, Ting-Yi Sung¹, Shiow-Lin Pan², Wei-Jan Huang³, Kai-Cheng Hsu⁴, Jui-Yi Hsu⁵, Tony Eight Lin⁶, Chia-Ming Hsu⁶, Chia-Ron Yang⁷

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.

MeSH terms

Androgen Antagonists
Androgens
Animals
Cell Line, Tumor
Cyclin-Dependent Kinase 8* / antagonists & inhibitors
Humans
Male
Neoplasm Metastasis
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / pathology
Signal Transduction

Substances

Androgen Antagonists
Androgens
CDK8 protein, human
Cyclin-Dependent Kinase 8