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Homo-PROTACs for the Chemical Knockdown of Cereblon.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2018-09-05 , DOI: 10.1021/acschembio.8b00693
Christian Steinebach 1 , Stefanie Lindner 2 , Namrata D Udeshi 3 , Deepak C Mani 3 , Hannes Kehm 2 , Simon Köpff 2 , Steven A Carr 3 , Michael Gütschow 1 , Jan Krönke 2
Affiliation  

The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide, all approved for the treatment of multiple myeloma, induce targeted ubiquitination and degradation of Ikaros (IKZF1) and Aiolos (IKZF3) via the cereblon (CRBN) E3 ubiquitin ligase. IMiD-based proteolysis-targeting chimeras (PROTACs) can efficiently recruit CRBN to a protein of interest, leading to its ubiquitination and proteasomal degradation. By linking two pomalidomide molecules, we designed homobifunctional, so-called homo-PROTACs and investigated their ability to induce self-directed ubiquitination and degradation. The homodimerized compound 15a was characterized as a highly potent and efficient CRBN degrader with only minimal effects on IKZF1 and IKZF3. The cellular selectivity of 15a for CRBN degradation was confirmed at the proteome level by quantitative mass spectrometry. Inactivation by compound 15a did not affect proliferation of different cell lines, prevented pomalidomide-induced degradation of IKZF1 and IKZF3, and antagonized the effects of pomalidomide on multiple myeloma cells. Homobifunctional CRBN degraders will be useful tools for future biomedical investigations of CRBN-related signaling and may help to further elucidate the molecular mechanism of thalidomide analogues.

中文翻译:

用于赛百隆化学击倒的均质PROTAC。

沙利度胺,来那度胺和泊马利度胺的免疫调节药物(IMiDs)均已批准用于治疗多发性骨髓瘤,它们通过大脑(CRBN)E3泛素连接酶诱导了Ikaros(IKZF1)和Aiolos(IKZF3)的靶向泛素化和降解。基于IMiD的蛋白水解靶向嵌合体(PROTAC)可以有效地将CRBN募集到目标蛋白中,从而导致其泛素化和蛋白酶体降解。通过连接两个pomalidomide分子,我们设计了同双功能的所谓同质PROTAC,并研究了它们诱导自定向泛素化和降解的能力。均二聚的化合物15a被表征为高效,高效的CRBN降解剂,对IKZF1和IKZF3的影响很小。通过定量质谱在蛋白质组水平上证实了15a对CRBN降解的细胞选择性。化合物15a的失活不会影响不同细胞系的增殖,不会阻止pomalidomide诱导的IKZF1和IKZF3降解,并且拮抗pomalidomide对多发性骨髓瘤细胞的作用。同功能的CRBN降解物将是用于CRBN相关信号转导的未来生物医学研究的有用工具,并可能有助于进一步阐明沙利度胺类似物的分子机制。
更新日期:2018-08-17
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