Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong 266003, China.
Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong 266003, China.
J Med Chem. 2023 Aug 24;66(16):11158-11186. doi: 10.1021/acs.jmedchem.3c00585. Epub 2023 Aug 9.
We report small molecular PROTAC compounds targeting the androgen receptor N-terminal domain (AR-NTD), which were obtained by tethering AR-NTD antagonists and different classes of E3 ligase ligands through chemical linkers. A representative compound, , effectively induces degradation of both AR-FL and AR-V7 and is more potent than the corresponding antagonist against prostate cancer (PC) cells in vitro. We have shown that the degradation of AR-FL and AR-V7 proteins by can suppress the expression of AR downstream proteins and induce PC cell apoptosis. achieves 40.5% oral bioavailability in mice and 69.3% in beagle dogs. In a LNCaP xenograft model study, was also proved to be an efficacious PROTAC degrader, resulting in 76% tumor growth inhibition after oral administration of a dose of 60 mg/kg. This study indicates that is a promising AR-NTD PROTAC for the treatment of AR-FL- and AR-V7-dependent tumors.
我们报告了通过化学连接子将雄激素受体 N 端结构域（AR-NTD）拮抗剂和不同类别的 E3 连接酶配体连接起来而获得的靶向 AR-NTD 的小分子 PROTAC 化合物。代表性化合物 能够有效诱导 AR-FL 和 AR-V7 的降解，并且比相应的拮抗剂对体外前列腺癌（PC）细胞更有效。我们已经表明， 通过 降解 AR-FL 和 AR-V7 蛋白可以抑制 AR 下游蛋白的表达并诱导 PC 细胞凋亡。 在小鼠中达到 40.5%的口服生物利用度，在比格犬中达到 69.3%。在 LNCaP 异种移植模型研究中， 也被证明是一种有效的 PROTAC 降解剂，口服 60mg/kg 剂量后可抑制 76%的肿瘤生长。这项研究表明， 是一种有前途的 AR-NTD PROTAC，可用于治疗依赖 AR-FL 和 AR-V7 的肿瘤。
