Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer
Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer
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DOI：
10.1021/acs.jmedchem.8b01631
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发表时间：
2019-01-24
影响因子：
7.3
通讯作者：
Wang, Shaomeng
中科院分区：
文献类型：
--
作者：
Han, Xin;Wang, Chao;Wang, Shaomeng
我们在此报道了高效的PROTAC雄激素受体（AR）降解剂的发现，例如化合物34 （ARD-69）。在AR阳性前列腺癌细胞系中，ARD-69以剂量和时间依赖的方式诱导AR蛋白降解。ARD-69在LNCaP、VCaP和22Rv1 AR+前列腺癌细胞株中的DC50值分别为0.86、0.76和10.4 nM。在这些前列腺癌细胞系中，ARD-69能够将AR蛋白水平降低约95%，并有效抑制AR调控基因的表达。ARD-69能有效抑制AR阳性前列腺癌细胞系的细胞生长，比AR拮抗剂强100倍。单剂量ARD-69可有效降低小鼠异种移植肿瘤组织中AR蛋白的水平。进一步优化ARD-69可能最终导致AR+去势抵抗性前列腺癌的新疗法。
We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.