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

  • Eur J Med Chem. 2022 Jan 5;227:113922. doi: 10.1016/j.ejmech.2021.113922.
Rong Hu  1 ,  Wan-Li Wang  1 ,  Ying-Yue Yang  1 ,  Xia-Tong Hu  1 ,  Qi-Wei Wang  2 ,  Wei-Qiong Zuo  2 ,  Ying Xu  3 ,  Qiang Feng  4 ,  Ning-Yu Wang  5
Affiliations
  • 1. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China.
  • 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, And Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.
  • 3. School of Chemical Engineering, Northwest University, No.229 North Taibai Road, Xi'an, Shaanxi, 710069, PR China.
  • 4. College of Chemistry and Life Science, Chengdu Normal University, Chengdu, China. Electronic address: [email protected].
  • 5. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China. Electronic address: [email protected].
PMID: 34700270 DOI: 10.1016/j.ejmech.2021.113922
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 (DC50) and maximum degradation (Dmax) > 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.

Keywords
AR-Positive prostate cancer; Antiproliferative; BRD4; Proteolysis targeting chimeras.
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