1135009-39-0Relevant academic research and scientific papers
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
, (2020)
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.
6-, 7-, or 8-Substituted Quinazolinone Derivatives and Compositions Comprising and Methods of Using the Same
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Page/Page column 36, (2009/04/24)
Provided are quinazolinone compounds, and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use, and pharmaceutical compositions of these compounds are disclosed.
