1. Identification of a selective BRD4 PROTAC with potent antiproliferative effects in AR-positive prostate cancer based on a dual BET/PLK1 inhibitor.
- Author
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Hu, Rong, Wang, Wan-Li, Yang, Ying-Yue, Hu, Xia-Tong, Wang, Qi-Wei, Zuo, Wei-Qiong, Xu, Ying, Feng, Qiang, and Wang, Ning-Yu
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PROSTATE cancer , *ANTINEOPLASTIC agents , *CELL cycle , *CANCER cells , *CELL lines , *PROTEOLYSIS , *PROSTATE-specific antigen - Abstract
BRD4-targeted proteolysis targeting chimera (PROTAC) have exhibited promising in vitro and in vivo anticancer activity in a number of cancer models. However, the clinical development of current reported BRD4-PROTACs have stagnated, largely due to the safety risks caused by their poor degradation selectivity. In this study, we designed and synthesized a series of PROTACs based on our recently reported dual BET/PLK1 inhibitor WNY0824 , which led to the discovery of an isoform-selective and potent BRD4-PROTAC 12a (WWL0245). WWL0245 exhibited excellent selective cytotoxicity in the BETi sensitive cancer cell lines, including AR-positive prostate cancer cell lines. It could also efficiently induce ubiquitin-proteasomal degradation of BRD4 in AR-positive prostate cancer cell lines, with sub-nanomolar half-maximal degrading concentration (DC 50) and maximum degradation (D max) > 99%. Moreover, WWL0245 induced cell cycle arrest at the G0/G1 phase and apoptosis in AR-positive prostate cancer by downregulation of the protein levels of AR, PSA and c-Myc as well as transcriptionally suppressed AR-regulated genes. WWL0245 was thus expected to be developed as a promising drug candidate for AR-positive prostate cancer and a valuable tool compound to study the biological function of BRD4. [Display omitted] • A series of PROTACs were designed and synthesized based on the dual BET/PLK1 inhibitor WNY0824. • 12a (WWL0245) is a potent and highly selective BRD4-PROTAC. • 12a exhibited better antiproliferative activity in AR-positive prostate cancer cells than WNY0824. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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