Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras.

Abstract

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.

• Authors: Akshay D Takwale, Seung-Hyun Jo, Yeong Uk Jeon, Hyung Soo Kim, Choong Hoon Shin, Heung Kyoung Lee, Sunjoo Ahn, Chong Ock Lee, Jae Du Ha, Jeong-Hoon Kim, Jong Yeon Hwang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 208 Pg. 112769 (Dec 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32961381 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• AR protein, human
• AR protein, mouse
• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Crbn protein, mouse
• Piperazines
• Receptors, Androgen

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, therapeutic use)
• Cell Line, Tumor
• Humans
• Male
• Mice, Inbred ICR
• Mice, SCID
• Microsomes, Liver (metabolism)
• Neoplasms (drug therapy)
• Piperazines (chemical synthesis, pharmacokinetics, therapeutic use)
• Proteolysis (drug effects)
• Receptors, Androgen (chemistry, metabolism)
• Xenograft Model Antitumor Assays