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Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR plus Human Prostate Cancer

文献类型：期刊论文

作者Xiang, Weiguo22; Zhao, Lijie22; Han, Xin19,20,21,22; Xu, Tianfeng16,17,18,22; Kregel, Steven13,14,15; Wang, Mi22; Miao, Bukeyan22; Qin, Chong10,11,12,22; Wang, Mingliang8,9,22; McEachern, Donna22
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2023-09-08
卷号66期号:18页码:13280-13303
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01264
通讯作者Wang, Shaomeng(Shaomeng@umich.edu)
英文摘要We report herein the discovery and extensive characterization of ARD-1676, a highly potent and orally efficacious PROTAC degrader of the androgen receptor (AR). ARD-1676 was designed using a new class of AR ligands and a novel cereblon ligand. It has DC50 values of 0.1 and 1.1 nM in AR+ VCaP and LNCaP cell lines, respectively, and IC50 values of 11.5 and 2.8 nM in VCaP and LNCaP cell lines, respectively. ARD-1676 effectively induces degradation of a broad panel of clinically relevant AR mutants. ARD-1676 has an oral bioavailability of 67, 44, 31, and 99% in mice, rats, dogs, and monkeys, respectively. Oral administration of ARD-1676 effectively reduces the level of AR protein in the VCaP tumor tissue in mice and inhibits tumor growth in the VCaP mouse xenograft tumor model without any sign of toxicity. ARD-1676 is a highly promising development candidate for the treatment of AR+ human prostate cancer.
WOS关键词ANDROGEN-RECEPTOR ; PROTEIN ; LIGASE ; ROUTE
资助项目Oncopia Therapeutics Inc., Proteovant Therapeutics Inc. ; National Cancer Institute/NIH[P50 CA186786] ; University of Michigan Comprehensive Cancer Center Core Grant from the National Cancer Institute, NIH[P30CA046592]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:001065437700001
源URL[http://119.78.100.183/handle/2S10ELR8/307146]  
专题中国科学院上海药物研究所
通讯作者Wang, Shaomeng
作者单位1.Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA
2.Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA
3.Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
4.Oncopia Therapeut Inc, Malvern, PA 19355 USA
5.Univ Michigan, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA
6.Univ Tennessee, Coll Pharm, Dept Pharmaceut Sci, Hlth Sci Ctr, Memphis, TN 38163 USA
7.Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA
8.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai, Peoples R China
9.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
10.Pilot Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao 266137, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Xiang, Weiguo,Zhao, Lijie,Han, Xin,et al. Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR plus Human Prostate Cancer[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(18):13280-13303.
APA Xiang, Weiguo.,Zhao, Lijie.,Han, Xin.,Xu, Tianfeng.,Kregel, Steven.,...&Wang, Shaomeng.(2023).Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR plus Human Prostate Cancer.JOURNAL OF MEDICINAL CHEMISTRY,66(18),13280-13303.
MLA Xiang, Weiguo,et al."Discovery of ARD-1676 as a Highly Potent and Orally Efficacious AR PROTAC Degrader with a Broad Activity against AR Mutants for the Treatment of AR plus Human Prostate Cancer".JOURNAL OF MEDICINAL CHEMISTRY 66.18(2023):13280-13303.

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来源：上海药物研究所

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