Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC)
| Autor: | Chun Wu, Y. Zhou, Chenchang Li, Baijun Dong, Wei Xue, Hongwu Chen, Junjian Wang, Chao Wang, Yan Zhang, Qiuping Xiang, Lingjiao Zou, Ming Song, Zhang Maofeng, Xiaoqian Xue, Xishan Wu, Cheng Zhang, Ke Ding, Donghai Wu, Yong Xu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Models Molecular BRD4 Antineoplastic Agents Cell Cycle Proteins Substrate Specificity 03 medical and health sciences chemistry.chemical_compound Prostate cancer Mice Structure-Activity Relationship 0302 clinical medicine Drug Discovery medicine Structure–activity relationship Animals Humans Isoxazole Tumor Stem Cell Assay Cell growth Drug discovery Nuclear Proteins Proteins Isoxazoles medicine.disease Xenograft Model Antitumor Assays Bromodomain Gene Expression Regulation Neoplastic Prostatic Neoplasms Castration-Resistant 030104 developmental biology chemistry 030220 oncology & carcinogenesis Drug Design Cancer research Molecular Medicine Cell Division Transcription Factors |
| Zdroj: | Journal of medicinal chemistry. 61(7) |
| ISSN: | 1520-4804 |
| Popis: | The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization, and evaluation of benzo[d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Cocrystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds, 6i (Y06036) and 7m (Y06137), bound to the BRD4(1) bromodomain with Kd values of 82 and 81 nM, respectively. They also exhibited high selectivity over other non-BET subfamily members. The compounds potently inhibited cell growth, colony formation, and the expression of AR, AR regulated genes, and MYC in prostate cancer cell lines. Compounds 6i and 7m also demonstrated therapeutic effects in a C4-2B CRPC xenograft tumor model in mice. These potent and selective BET inhibitors represent a new class of compounds for the development of potential... |
| Databáze: | OpenAIRE |
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