2. Academic Validation
  3. Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer

Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer

  • J Med Chem. 2019 Jan 24;62(2):941-964. doi: 10.1021/acs.jmedchem.8b01631.
Xin Han,  Chao Wang,  Chong Qin,  Weiguo Xiang,  Ester Fernandez-Salas,  Chao-Yie Yang,  Mi Wang,  Lijie Zhao,  Tianfeng Xu,  Krishnapriya Chinnaswamy,  James Delproposto,  Jeanne Stuckey,  Shaomeng Wang
PMID: 30629437 DOI: 10.1021/acs.jmedchem.8b01631
Abstract

We report herein the discovery of highly potent PROTAC degraders of Androgen Receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate Cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate Cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate Cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate Cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate Cancer.

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