Identification of a selective BRD4 PROTAC with potent antiproliferative effects in AR-positive prostate cancer based on a dual BET/PLK1 inhibitor
| Autor: | Ying-Yue Yang, Qi-Wei Wang, Ning-Yu Wang, Weiqiong Zuo, Rong Hu, Qiang Feng, Ying Xu, Wan-Li Wang, Xia-Tong Hu |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Male
BRD4 Cell cycle checkpoint Antineoplastic Agents Cell Cycle Proteins Protein Serine-Threonine Kinases PLK1 Structure-Activity Relationship Prostate cancer Downregulation and upregulation Proto-Oncogene Proteins Drug Discovery medicine Humans Protein Kinase Inhibitors Cell Proliferation Pharmacology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Proteolysis targeting chimera Prostatic Neoplasms Proteins Cancer General Medicine medicine.disease Apoptosis Proteolysis Cancer research Transcription Factors |
| Zdroj: | European Journal of Medicinal Chemistry. 227:113922 |
| ISSN: | 0223-5234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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