論文 - 詳細
| RRC ID | 81277 |
|---|---|
| 著者 | Wang C, Wang M, Wang Y, Rej RK, Aguilar A, Xu T, Bai L, Tošović J, McEachern D, Li Q, Sarkari F, Wen B, Sun D, Wang S. |
| タイトル | Discovery of CW-3308 as a Potent, Selective, and Orally Efficacious PROTAC Degrader of BRD9. |
| ジャーナル | J Med Chem |
| Abstract |
The bromodomain-containing protein BRD9 has emerged as an attractive therapeutic target. In the present study, we successfully identified a number of highly potent BRD9 degraders by using two different cereblon ligands developed in our laboratory. Further optimization led to the discovery of CW-3308 as a potent, selective, and orally bioavailable BRD9 degrader. It displayed degradation potency (DC50) < 10 nM and efficiency (Dmax) > 90% against BRD9 in the G401 rhabdoid tumor and HS-SY-II synovial sarcoma cell lines and had a high degradation selectivity over BRD7 and BRD4 proteins. CW-3308 achieved 91% of oral bioavailability in mice. A single oral dose efficiently reduced the BRD9 protein by >90% in the synovial sarcoma HS-SY-II xenograft tumor tissue. Oral administration effectively inhibited HS-SY-II xenograft tumor growth in mice. CW-3308 is a promising lead compound for further optimization and extensive evaluation for the treatment of synovial sarcoma, rhabdoid tumor, and other BRD9-dependent human diseases. |
| 公開日 | 2024-8-12 |
| DOI | 10.1021/acs.jmedchem.4c00971 |
| PMID | 39132814 |
| IF | 6.205 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 8 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HS-SY-II(RCB2231) |