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

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

  • Eur J Med Chem. 2021 Apr 15;216:113307. doi: 10.1016/j.ejmech.2021.113307.
Linrong Chen 1,  Liuquan Han 2,  Shujun Mao 2,  Ping Xu 2,  Xinxin Xu 2,  Ruibo Zhao 1,  Zhihua Wu 3,  Kai Zhong 4,  Guangliang Yu 5,  Xiaolei Wang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, 222 S. Tianshui Rd, Lanzhou, 730000, PR China.
  • 2 Suzhou Degen Bio-medical Co., Ltd, No.1 Huayun Road, SIP, Suzhou, 215000, PR China.
  • 3 School of Pharmacy, Lanzhou University, 222 S. Tianshui Rd, Lanzhou, 730000, PR China.
  • 4 Suzhou Degen Bio-medical Co., Ltd, No.1 Huayun Road, SIP, Suzhou, 215000, PR China. Electronic address: [email protected].
  • 5 Suzhou Degen Bio-medical Co., Ltd, No.1 Huayun Road, SIP, Suzhou, 215000, PR China. Electronic address: [email protected].
  • 6 State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, 222 S. Tianshui Rd, Lanzhou, 730000, PR China. Electronic address: [email protected].
PMID: 33652354 DOI: 10.1016/j.ejmech.2021.113307
Abstract

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.

Keywords

Androgen receptor; E3 ligand; Human prostate cancer; PROTAC; VHL ligand.

Figures
Products