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.
Journal of medicinal chemistry. 2023 Sep 08 [Epub ahead of print]
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
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States., Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, United States., Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States., Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States., Oncopia Therapeutics Inc, 2 West Liberty Blvd., Malvern, Pennsylvania 19355, United States.