[논문]Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras

Takwale, Akshay D.; Jo, Seung-Hyun; Jeon, Yeong Uk; Kim, Hyung Soo; Shin, Choong Hoon; Lee, Heung Kyoung; Ahn, Sunjoo; Lee, Chong Ock; Du Ha, Jae; Kim, Jeong-Hoon; Hwang, Jong Yeon

doi:10.1016/j.ejmech.2020.112769

[해외논문] Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras

European journal of medicinal chemistry, v.208, 2020년, pp.112769 -

Takwale, Akshay D. (Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology) , Jo, Seung-Hyun (Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology) , Jeon, Yeong Uk (Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology) , Kim, Hyung Soo (Department of Chemistry, Korea Univeristy) , Shin, Choong Hoon (Department of Chemistry, Sogang Univeristy) , Lee, Heung Kyoung (Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology) , Ahn, Sunjoo (Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology) , Lee, Chong Ock (Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology) , Du Ha, Jae (Therapeutics and Biotechnology Division, Korea Research Ins) , Kim, Jeong-Hoon , Hwang, Jong Yeon

Abstract ▼ AI-Helper

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. Highlights Induction of androgen receptor degradation mediated by cereblon E3 ligase. Inhibition of cell growth in AR-dependent prostate cancer cells. Good microsomal stability and in vivo PK properties. Effectively inhibit tumor growth by treatment with TD-802. Graphical abstract [DISPLAY OMISSION]

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