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.
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Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer.Mol Cancer Ther. 2018 Jul;17(7):1554-1565. doi: 10.1158/1535-7163.MCT-17-0945. Epub 2018 May 1. Mol Cancer Ther. 2018. PMID: 29716963 Free PMC article.
Exploitation of Castration-Resistant Prostate Cancer Transcription Factor Dependencies by the Novel BET Inhibitor ABBV-075.Mol Cancer Res. 2017 Jan;15(1):35-44. doi: 10.1158/1541-7786.MCR-16-0221. Epub 2016 Oct 5. Mol Cancer Res. 2017. PMID: 27707886
Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC).Clin Cancer Res. 2018 Jul 1;24(13):3149-3162. doi: 10.1158/1078-0432.CCR-17-3571. Epub 2018 Mar 19. Clin Cancer Res. 2018. PMID: 29555663
Role of BET proteins in castration-resistant prostate cancer.Drug Discov Today Technol. 2016 Mar;19:29-38. doi: 10.1016/j.ddtec.2016.07.001. Epub 2016 Jul 30. Drug Discov Today Technol. 2016. PMID: 27769354 Review.
BET bromodomain inhibitors--a novel epigenetic approach in castration-resistant prostate cancer.Cancer Biol Ther. 2014;15(12):1583-5. doi: 10.4161/15384047.2014.962297. Cancer Biol Ther. 2014. PMID: 25535892 Free PMC article. Review.