A novel cereblon modulator for targeted protein degradation

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Title
A novel cereblon modulator for targeted protein degradation
Author(s)
Sung Ah Kim; A Go; Seung-Hyun Jo; S J Park; Y U Jeon; J E Kim; H K Lee; C H Park; C O Lee; Sung Goo Park; P Kim; Byoung Chul Park; S Y Cho; Sunhong Kim; J D Ha; Jeong Hoon Kim; J Y Hwang
Bibliographic Citation
European Journal of Medicinal Chemistry, vol. 166, pp. 65-74
Publication Year
2019
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.
Keyword
BETCRBNIMiDsPROTAC
ISSN
0223-5234
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.ejmech.2019.01.023
Type
Article
Appears in Collections:
Division of Biomedical Research > Disease Target Structure Research Center > 1. Journal Articles
Critical Diseases Diagnostics Convergence Research Center > 1. Journal Articles
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