State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, 222 S. Tianshui Rd, Lanzhou, 730000, PR China.
Suzhou Degen Bio-medical Co., Ltd, No.1 Huayun Road, SIP, Suzhou, 215000, PR China.
Eur J Med Chem. 2021 Apr 15;216:113307. doi: 10.1016/j.ejmech.2021.113307. Epub 2021 Feb 23.
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.
雄激素受体（AR）是治疗前列腺癌的有效治疗靶点。我们在此报告了高效的蛋白酶靶向嵌合体（PROTAC）雄激素受体（AR）降解剂的设计、合成和生物学评价，例如化合物 A031。它可以在时间依赖性方式下诱导 VCaP 细胞系中 AR 蛋白的降解，实现 IC 50 值小于 0.25 μM。A031 的毒性比 EZLA 低 5 倍，半衰期（t 1/2）或清除率（Cl）适中。此外，它对斑马鱼移植的人前列腺癌（VCaP）的肿瘤生长具有显著的抑制作用。因此，A031 为开发治疗前列腺癌的新型药物提供了进一步的思路。
