Discovery of BWA-522, a First-in-Class and Orally Bioavailable PROTAC Degrader of the Androgen Receptor Targeting N-Terminal Domain for the Treatment of Prostate Cancer,Journal of Medicinal Chemistry

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Discovery of BWA-522, a First-in-Class and Orally Bioavailable PROTAC Degrader of the Androgen Receptor Targeting N-Terminal Domain for the Treatment of Prostate Cancer
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-08-09 , DOI: 10.1021/acs.jmedchem.3c00585
Bowen Zhang ₁ , Chang Liu ₁ , Zhenqian Yang ₁ , Sai Zhang _{1,

2} , Xiaolin Hu ₁ , Baohu Li ₁ , Mei Mao ₁ , Xiao Wang _{1,

2} , Zhuoyue Li _{1,

2} , Shumin Ma _{1,

2} , Siqi Zhang _{1,

2} , Chong Qin _{1,

2,

3}

Affiliation

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, BWA-522, 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 BWA-522 can suppress the expression of AR downstream proteins and induce PC cell apoptosis. BWA-522 achieves 40.5% oral bioavailability in mice and 69.3% in beagle dogs. In a LNCaP xenograft model study, BWA-522 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 BWA-522 is a promising AR-NTD PROTAC for the treatment of AR-FL- and AR-V7-dependent tumors.

中文翻译：

BWA-522 的发现，一种用于治疗前列腺癌的同类首创、口服生物可利用的雄激素受体 PROTAC 降解剂，靶向 N 端结构域

我们报道了靶向雄激素受体 N 末端结构域 (AR-NTD) 的小分子 PROTAC 化合物，这些化合物是通过化学接头连接 AR-NTD 拮抗剂和不同类别的 E3 连接酶配体而获得的。代表性化合物BWA-522可有效诱导 AR-FL 和 AR-V7 降解，并且在体外比相应的前列腺癌 (PC) 细胞拮抗剂更有效。我们发现， BWA-522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。BWA-522在小鼠中的口服生物利用度为 40.5%，在比格犬中的口服生物利用度为 69.3%。在 LNCaP 异种移植模型研究中，BWA-522也被证明是一种有效的 PROTAC 降解剂，口服 60 mg/kg 剂量后可抑制 76% 的肿瘤生长。这项研究表明，BWA-522是一种有前途的 AR-NTD PROTAC，用于治疗 AR-FL 和 AR-V7 依赖性肿瘤。

更新日期：2023-08-09

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