PUBLICATION
Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer
- Authors
- Chen, L., Han, L., Mao, S., Xu, P., Xu, X., Zhao, R., Wu, Z., Zhong, K., Yu, G., Wang, X.
- ID
- ZDB-PUB-210303-13
- Date
- 2021
- Source
- European Journal of Medicinal Chemistry 216: 113307 (Journal)
- Registered Authors
- Keywords
- Androgen receptor, E3 ligand, Human prostate cancer, PROTAC, VHL ligand
- MeSH Terms
-
- Androgen Receptor Antagonists/chemistry*
- Androgen Receptor Antagonists/pharmacokinetics
- Androgen Receptor Antagonists/pharmacology
- Androgen Receptor Antagonists/therapeutic use
- Animals
- Cell Line, Tumor
- Cell Survival/drug effects
- Drug Design
- Drug Evaluation, Preclinical
- Half-Life
- Humans
- Male
- Prostatic Neoplasms/drug therapy
- Prostatic Neoplasms/mortality
- Prostatic Neoplasms/pathology
- Proteolysis
- Rats
- Rats, Sprague-Dawley
- Receptors, Androgen/genetics
- Receptors, Androgen/metabolism*
- Structure-Activity Relationship
- Survival Rate
- Transplantation, Heterologous
- Zebrafish/growth & development
- Zebrafish/physiology
- PubMed
- 33652354 Full text @ Eur. J. Med. Chem.
Citation
Chen, L., Han, L., Mao, S., Xu, P., Xu, X., Zhao, R., Wu, Z., Zhong, K., Yu, G., Wang, X. (2021) Discovery of A031 as effective proteolysis targeting chimera (PROTAC) androgen receptor (AR) degrader for the treatment of prostate cancer. European Journal of Medicinal Chemistry. 216:113307.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping