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.
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