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.

BRD4靶向蛋白水解靶向嵌合体（PROTAC）在许多癌症模型中表现出有希望的体外和体内抗癌活性。然而，目前报道的 BRD4-PROTACs 的临床发展停滞不前，主要是由于其降解选择性差导致的安全风险。在这项研究中，我们基于我们最近报道的双 BET/PLK1 抑制剂WNY0824设计并合成了一系列 PROTAC ，从而发现了同种型选择性和有效的 BRD4-PROTAC 12a ( WWL0245)。WWL0245在 BETi 敏感癌细胞系（包括 AR 阳性前列腺癌细胞系）中表现出优异的选择性细胞毒性。它还可以有效地诱导 AR 阳性前列腺癌细胞系中 BRD4 的泛素-蛋白酶体降解，亚纳摩尔半最大降解浓度 (DC ₅₀ ) 和最大降解 (D _max ) > 99%。此外，WWL0245通过下调 AR、PSA 和 c-Myc 的蛋白质水平以及转录抑制的 AR 调节基因诱导 AR 阳性前列腺癌的 G0/G1 期细胞周期停滞和细胞凋亡。WWL0245因此，有望将其开发为 AR 阳性前列腺癌的有希望的候选药物和研究 BRD4 生物学功能的有价值的工具化合物。