A novel cereblon modulator for targeted protein degradation

被引：41

作者：

Kim, Sung Ah ^{[1
,2
]}

Go, Ara ^{[3
]}

Jo, Seung-Hyun ^{[1
,2
]}

Park, Sun Jun ^{[3
]}

Jeon, Young Uk ^{[3
]}

Kim, Ji Eun ^{[3
]}

Lee, Heung Kyoung ^{[3
]}

Park, Chi Hoon ^{[3
,4
]}

Lee, Chong-Ock ^{[3
]}

Park, Sung Goo ^{[1
,2
]}

Kim, Pilho ^{[3
,4
]}

Park, Byoung Chul ^{[1
,5
]}

Cho, Sung Yun ^{[3
]}

Kim, Sunhong ^{[1
,6
]}

Ha, Jae Du ^{[3
]}

Kim, Jeong-Hoon ^{[1
,2
]}

Hwang, Jong Yeon ^{[3
,4
]}

机构：

[1] Korea Res Inst Biosci & Biotechnol, Dis Target Struct Res Ctr, Daejeon 34141, South Korea

[2] Univ Sci & Technol, Dept Funct Genom, Daejeon 34113, South Korea

[3] Korea Res Inst Chem Technol, Therapeut & Biotechnol Div, Daejeon 34119, South Korea

[4] Univ Sci & Technol, Dept Med Chem & Pharmacol, Daejeon 34113, South Korea

[5] Univ Sci & Technol, Dept Bioanalyt Sci, Daejeon 34113, South Korea

[6] Univ Sci & Technol, Dept Biomol Sci, Daejeon 34113, South Korea

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 166卷

关键词：

CRBN; BET; PROTAC; IMiDs; BET BROMODOMAIN PROTEIN; MULTIPLE-MYELOMA; SELECTIVE DEGRADATION; PROTAC DESIGN; THALIDOMIDE; UBIQUITINATION; DISCOVERY; GROWTH; BRD4;

D O I：

10.1016/j.ejmech.2019.01.023

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页码：65 / 74

页数：10

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