期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 208, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112769
关键词
Androgen receptor; Proteolysis targeting chimera; Prostate cancer; Cereblon; TD-106
资金
- National Research Council of Science and Technology [CAP-15-11-KRICT]
- National Research Foundation, Ministry of Science and ICT and future planning [NRF-2019M3E5D4069882]
- KRIBB Initiative program
- National Research Foundation of Korea [2019M3E5D4069882] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study. (c) 2020 Elsevier Masson SAS. All rights reserved.
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