Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 13, Pages 8822-8843Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c00405
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We report the discovery of ARD-2051, a highly potent and orally efficacious androgen receptor (AR) proteolysis-targeting chimera degrader. ARD-2051 demonstrates strong AR protein degradation activity and effectively suppresses AR-regulated genes in prostate cancer cell lines. It shows good oral bioavailability and pharmacokinetic profile in animal models. In addition, ARD-2051 inhibits tumor growth and exhibits no signs of toxicity in mice, making it a promising therapeutic option for AR+ human cancers.
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.
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