Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer

• DOI: 10.1016/j.ejmech.2021.113307
• Publication Date: 2021-02-23T21:43:11Z
• Authors: Linrong Chen; Liuquan Han; Shujun Mao; Ping Xu; Xinxin Xu; Ruibo Zhao; Zhihua Wu; Kai Zhong; Guangliang Yu; Xiaolei Wang
• Keywords: Male; 0301 basic medicine; Cell Survival; Transplantation, Heterologous; Drug Evaluation, Preclinical; Prostatic Neoplasms; Rats; 3. Good health; Rats, Sprague-Dawley; Survival Rate; Structure-Activity Relationship; 03 medical and health sciences; Receptors, Androgen; Cell Line, Tumor; Drug Design; Proteolysis; Androgen Receptor Antagonists; Animals; Humans; Zebrafish; Half-Life

Androgen receptor (AR) is an effective therapeutic target for the treatment of prostate cancer. We report herein the design, synthesis, and biological evaluation of highly effective proteolysis targeting chimeras (PROTAC) androgen receptor (AR) degraders, such as compound A031. It could induce the degradation of AR protein in VCaP cell lines in a time-dependent manner, achieving the IC 50 value of less than 0.25 μM. The A031 is 5 times less toxic than EZLA and works with an appropriate half-life (t 1/2) or clearance rate (Cl). Also, it has a significant inhibitory effect on tumor growth in zebrafish transplanted with human prostate cancer (VCaP). Therefore, A031 provides a further idea of developing novel drugs for prostate cancer.