Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Mar 27;molcanther.0578.2019.
doi: 10.1158/1535-7163.MCT-19-0578. Online ahead of print.

Novel Dual BET and PLK1 Inhibitor WNY0824 Exerts Potent Anti-Tumor Effects in CRPC by Inhibiting Transcription Factor Function and Inducing Mitotic Abnormality

Affiliations

Novel Dual BET and PLK1 Inhibitor WNY0824 Exerts Potent Anti-Tumor Effects in CRPC by Inhibiting Transcription Factor Function and Inducing Mitotic Abnormality

Ying Xu et al. Mol Cancer Ther. .

Abstract

Castration-resistant prostate cancer (CRPC) is a lethal disease with few treatment alternatives once patients become resistant to second-generation anti-androgens. In CRPC, BET proteins are key regulators of AR- and MYC-mediated transcription, while the PLK1 inhibitor potentially downregulates AR and MYC besides influencing the cell cycle. Therefore, synchronous inhibition of BET and PLK1 would be a promising approach for CRPC therapy. This study developed a dual BET and PLK1 inhibitor WNY0824 with nanomolar and equipotent inhibition of BRD4 and PLK1. In vitro, WNY0824 exhibited excellent anti-proliferation activity on AR-positive CRPC cells and induced apoptosis. These activities are attributable to its disruption of the AR-transcriptional program and the inhibition of the ETS pathway. Furthermore, WNY0824 downregulated MYC and induced mitotic abnormality. In vivo, oral WNY0824 administration suppressed tumor growth in the CRPC xenograft model of enzalutamide resistance. These findings suggest that WNY0824 is a selective dual BET and PLK1 inhibitor with potent anti-CRPC oncogenic activity and provides insights into the development of other novel dual BET- and PLK1-inhibiting drugs.

Similar articles

See all similar articles

LinkOut - more resources

Feedback