Discovery of ARD-2051 as a Potent and Orally Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer

被引：23

作者：

Han, Xin ^{[1
,2
]}

Zhao, Lijie ^{[1
,2
]}

Xiang, Weiguo ^{[1
,2
]}

Miao, Bukeyan ^{[1
,2
]}

Qin, Chong ^{[1
,2
]}

Wang, Mi ^{[1
,2
]}

Xu, Tianfeng ^{[1
,2
]}

McEachern, Donna ^{[1
,2
]}

Lu, Jianfeng ^{[1
,2
]}

Wang, Yu ^{[1
,2
]}

Metwally, Hoda ^{[1
,2
]}

Yang, Chao-Yie ^{[1
,2
]}

Kirchhoff, Paul D. D. ^{[1
,2
]}

Wang, Lu ^{[5
]}

Matvekas, Aleksas ^{[5
]}

Takyi-Williams, John ^{[5
]}

Wen, Bo ^{[5
]}

Sun, Duxin ^{[5
]}

Ator, Mark ^{[6
]}

Mckean, Robert ^{[6
]}

Wang, Shaomeng ^{[1
,2
,3
,4
]}

机构：

[1] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA

[4] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

[5] Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA

[6] Oncopia Therapeut Inc, Malvern, PA 19355 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 13期

关键词：

PROTEIN-DEGRADATION; UBIQUITINATION; MOLECULES;

D O I：

10.1021/acs.jmedchem.3c00405

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the discovery of ARD-2051as a potent and orally efficaciousandrogen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051achieves DC50 values of 0.6 nM and D (max) >90% in inducing AR protein degradation in both theLNCaPand VCaP prostate cancer cell lines, potently and effectively suppressesAR-regulated genes, and inhibits cancer cell growth. ARD-2051 achievesa good oral bioavailability and pharmacokinetic profile in mouse,rat, and dog. A single oral dose of ARD-2051 strongly reduces AR proteinand suppresses AR-regulated gene expression in the VCaP xenografttumor tissue in mice. Oral administration of ARD-2051 effectivelyinhibits VCaP tumor growth and causes no signs of toxicity in mice.ARD-2051 is a promising AR degrader for advanced preclinical developmentfor the treatment of AR+ human cancers.

引用

页码：8822 / 8843

页数：22

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