- March 23, 2023
![Metastatic castration-resistant prostate cancer (mCRPC)](https://www.medicilon.com/blog/wp-content/uploads/2023/03/Metastatic-castration-resistant-prostate-cancer-mCRPC-1024x579.jpg)
Proteolysis targeting chimeras (PROTACs)
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules with three chemical elements: a ligand binding to a target protein of interest, a ligand binding to and recruiting E3 ubiquitin ligase complex, and a linker for conjugating these two ligands together. PROTAC is a chemical knockdown strategy that degrades the target protein through the ubiquitin-proteasome system. Unlike traditional inhibitors’ competitive- and occupancy-driven process, PROTACs are catalytic in their mode of action, which can promote target protein degradation at low exposures.
PROTAC androgen receptor (AR) degraders
![Chemical-structure-of-ARD-2585](https://www.medicilon.com/blog/wp-content/uploads/2023/03/Chemical-structure-of-ARD-2585.jpg)
In vivo efficacy evaluation of ARD-2585
![Efficacy study of ARD-2585 in the VCaP xenograft tumor model with Enzalutamide included as the control](https://www.medicilon.com/blog/wp-content/uploads/2023/03/Efficacy-study-of-ARD-2585-in-the-VCaP-xenograft-tumor-model-with-Enzalutamide-included-as-the-control-1024x290.jpg)
Plasma stability studies of ARD-2585
![Pk-of-compounds-26,35,and-40-45-in-mice.jpg](https://www.medicilon.com/blog/wp-content/uploads/2023/03/pk-of-compounds-2635and-40-45-in-mice-1024x294.jpg)
![Tissue-distribution-studies-of-ARD-2585-in-mice-bearing-VCaP-Tumors.jpg](https://www.medicilon.com/blog/wp-content/uploads/2023/03/tissue-distribution-studies-of-ARD-2585-in-mice-bearing-VCaP-Tumors-1024x609.jpg)
Summary
References:
[1] Weiguo Xiang, et al. Discovery of ARD-2585 as an Exceptionally Potent and Orally Active PROTAC Degrader of Androgen Receptor for the Treatment of Advanced Prostate Cancer. J Med Chem. 2021 Sep 23;64(18):13487-13509. doi: 10.1021/acs.jmedchem.1c00900.
[2] Xiaojuan Jia, et al. Targeting androgen receptor degradation with PROTACs from bench to bedside. Biomed Pharmacother. 2023 Feb;158:114112. DOI: 10.1016/j.biopha.2022.114112
[3] Thi-Thao-Linh Nguyen, et al. Development of an LC-MS/MS Method for ARV-110, a PROTAC Molecule, and Applications to Pharmacokinetic Studies. Molecules. 2022 Mar 18;27(6):1977. doi: 10.3390/molecules27061977.
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#pharmacokinetics
#androgen receptor
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