Identification of a selective BRD4 PROTAC with potent antiproliferative effects in AR-positive prostate cancer based on a dual BET/PLK1 inhibitor

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 (DC₅₀) 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.