Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands
| Autor: | Shaomeng Wang, Tianfeng Xu, Jeanne A. Stuckey, Mi Wang, Bukeyan Miao, Weiguo Xiang, Krishnapriya Chinnaswamy, Chong Qin, Chao Yie Yang, Xin Han, Lijie Zhao |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Proteasome Endopeptidase Complex Ubiquitin-Protein Ligases Ligands 01 natural sciences Small Molecule Libraries 03 medical and health sciences Prostate cancer Piperidines LNCaP Gene expression Drug Discovery medicine Androgen Receptor Antagonists Tumor Cells Cultured Humans 030304 developmental biology Cell Proliferation 0303 health sciences biology Chemistry Ubiquitin Proteolysis targeting chimera Antagonist Prostatic Neoplasms Ligand (biochemistry) medicine.disease 0104 chemical sciences Ubiquitin ligase Androgen receptor 010404 medicinal & biomolecular chemistry Receptors Androgen Von Hippel-Lindau Tumor Suppressor Protein Drug Design Proteolysis biology.protein Cancer research Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 62(24) |
| ISSN: | 1520-4804 |
| Popis: | Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of 11 (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50 values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research. |
| Databáze: | OpenAIRE |
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