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.
Xin HanLijie ZhaoWeiguo XiangBukeyan MiaoChong QinMi WangTianfeng XuDonna McEachernJianfeng LuYu WangHoda MetwallyChao-Yie YangPaul D KirchhoffLu WangAleksas MatvekasJohn Takyi-WilliamsBo WenDuxin SunMark AtorRobert MckeanShaomeng WangPublished in: Journal of medicinal chemistry (2023)
We report the discovery of ARD-2051 as a potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 achieves DC 50 values of 0.6 nM and D max >90% in inducing AR protein degradation in both the LNCaP and VCaP prostate cancer cell lines, potently and effectively suppresses AR-regulated genes, and inhibits cancer cell growth. ARD-2051 achieves a good oral bioavailability and pharmacokinetic profile in mouse, rat, and dog. A single oral dose of ARD-2051 strongly reduces AR protein and suppresses AR-regulated gene expression in the VCaP xenograft tumor tissue in mice. Oral administration of ARD-2051 effectively inhibits VCaP tumor growth and causes no signs of toxicity in mice. ARD-2051 is a promising AR degrader for advanced preclinical development for the treatment of AR+ human cancers.
Keyphrases
- prostate cancer
- gene expression
- small molecule
- endothelial cells
- radical prostatectomy
- signaling pathway
- oxidative stress
- transcription factor
- dna methylation
- high throughput
- metabolic syndrome
- stem cells
- type diabetes
- drug delivery
- immune response
- mesenchymal stem cells
- photodynamic therapy
- cell therapy
- insulin resistance
- young adults
- wild type
- bioinformatics analysis