发现 ARD-1676 作为一种高效和口服有效的 AR PROTAC 降解剂，广泛作用于 AR 突变体，用于治疗 AR+ 人类前列腺癌。
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 + Human Prostate Cancer.
发表日期：2023 Sep 08
作者：
Weiguo Xiang, Lijie Zhao, Xin Han, Tianfeng Xu, Steven Kregel, Mi Wang, Bukeyan Miao, Chong Qin, Mingliang Wang, Donna McEachern, Jianfeng Lu, Longchuan Bai, Chao-Yie Yang, Paul D Kirchhoff, John Takyi-Williams, Lu Wang, Bo Wen, Duxin Sun, Mark Ator, Robert Mckean, Arul M Chinnaiyan, Shaomeng Wang
来源：
PHARMACOLOGY & THERAPEUTICS
摘要：
本文报道了ARD-1676的发现和广泛的特性研究，它是一种高效的口服蛋白质降解酶（PROTAC）降解剂，主要作用于雄激素受体（AR）。ARD-1676是使用一类新型AR配体和一种新型脑脊髓灰质空白卷曲蛋白（cereblon）配体设计的。在AR+ VCaP和LNCaP细胞系中，其DC50值分别为0.1纳摩尔和1.1纳摩尔，IC50值分别为11.5纳摩尔和2.8纳摩尔。ARD-1676有效地引起了一系列临床相关的AR突变体的降解。ARD-1676在小鼠、大鼠、狗和猴子中的口服生物利用度分别为67％、44％、31％和99％。在小鼠中，口服ARD-1676有效降低了VCaP肿瘤组织中的AR蛋白水平，并且在VCaP小鼠异种移植肿瘤模型中抑制了肿瘤生长，没有表现出任何毒性迹象。ARD-1676是治疗AR+人类前列腺癌的一个高度有希望的开发候选药物。
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.