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Title 

A novel cereblon modulator for targeted protein degradation

Authors 

Sung Ah KimA GoSeung-Hyun JoS J ParkY U JeonJ E KimH K LeeC H ParkC O LeeSung Goo ParkP KimByoung Chul ParkS Y ChoSunhong KimJ D HaJeong Hoon KimJ Y Hwang

Publisher 

Elsevier

Issue Date 

2019

Citation 

European Journal of Medicinal Chemistry

Keywords 

BETCRBNIMiDsPROTAC

Abstract 

Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells in vitro as well as in vivo. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET inhibitor, JQ1 efficiently induce BET protein degradation in the prostate cancer cell line 22Rv1. Consequently, cell proliferation is inhibited due to suppressed C-MYC transcription. These results, therefore, firmly suggest that the newly synthesized IMiD analog, TD-106, is a novel CRBN modulator that can be used for targeted protein degradation.

URI 

https://doi.org/10.1016/j.ejmech.2019.01.023

ISSN 

0223-5234

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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