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Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-05 , DOI: 10.1021/acs.jmedchem.9b01393
Xin Han , Lijie Zhao 1 , Weiguo Xiang , Chong Qin , Bukeyan Miao , Tianfeng Xu , Mi Wang , Chao-Yie Yang , Krishnapriya Chinnaswamy , Jeanne Stuckey , Shaomeng Wang
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2019-12-05 , DOI: 10.1021/acs.jmedchem.9b01393
Xin Han , Lijie Zhao 1 , Weiguo Xiang , Chong Qin , Bukeyan Miao , Tianfeng Xu , Mi Wang , Chao-Yie Yang , Krishnapriya Chinnaswamy , Jeanne Stuckey , Shaomeng Wang
Affiliation
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Androgen receptor (AR) is a validated therapeutic target for the treatment of metastatic castration-resistant prostate cancer (mCRPC). We report herein our design, synthesis, and biological characterization of highly potent small-molecule proteolysis targeting chimera (PROTAC) AR degraders using a potent AR antagonist and E3 ligase ligands with weak binding affinities to VHL protein. Our study resulted in the discovery of 11 (ARD-266), which effectively induces degradation of AR protein in AR-positive (AR+) LNCaP, VCaP, and 22Rv1 prostate cancer cell lines with DC50 values of 0.2-1 nM. ARD-266 is capable of reducing the AR protein level by >95% in these AR+ prostate cancer cell lines and effectively reduces AR-regulated gene expression suppression. For the first time, we demonstrated that an E3 ligand with micromolar binding affinity to its E3 ligase complex can be successfully employed for the design of highly potent and efficient PROTAC degraders and this finding may have a significant implication for the field of PROTAC research.
中文翻译:
通过使用弱结合亲和力VHL E3连接酶配体发现雄激素受体(AR)的高效强PROTAC降解剂。
雄激素受体(AR)是用于治疗转移性去势抵抗性前列腺癌(mCRPC)的有效治疗靶标。我们在这里报告我们的设计,合成和针对高效的小分子蛋白水解嵌合体(PROTAC)AR降解体的设计,合成和生物学表征,使用一种有效的AR拮抗剂和对VHL蛋白具有弱结合亲和力的E3连接酶配体。我们的研究导致发现11(ARD-266),它可以有效诱导AR阳性(AR +)LNCaP,VCaP和22Rv1前列腺癌细胞系中DC蛋白值为0.2-1 nM的AR蛋白降解。ARD-266能够在这些AR +前列腺癌细胞系中将AR蛋白水平降低> 95%,并有效降低AR调控的基因表达抑制。首次,
更新日期:2019-12-06
中文翻译:
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通过使用弱结合亲和力VHL E3连接酶配体发现雄激素受体(AR)的高效强PROTAC降解剂。
雄激素受体(AR)是用于治疗转移性去势抵抗性前列腺癌(mCRPC)的有效治疗靶标。我们在这里报告我们的设计,合成和针对高效的小分子蛋白水解嵌合体(PROTAC)AR降解体的设计,合成和生物学表征,使用一种有效的AR拮抗剂和对VHL蛋白具有弱结合亲和力的E3连接酶配体。我们的研究导致发现11(ARD-266),它可以有效诱导AR阳性(AR +)LNCaP,VCaP和22Rv1前列腺癌细胞系中DC蛋白值为0.2-1 nM的AR蛋白降解。ARD-266能够在这些AR +前列腺癌细胞系中将AR蛋白水平降低> 95%,并有效降低AR调控的基因表达抑制。首次,