小脑
泛素连接酶
邻苯二甲酰亚胺
化学
泛素
溴尿嘧啶
小分子
细胞生物学
蛋白质降解
癌细胞
相扑蛋白
辅活化剂
体内
化学生物学
生物化学
生物
转录因子
癌症
生物物理学
体外
乙酰化
表观遗传学
遗传学
基因
生物技术
作者
Georg E. Winter,Dennis L. Buckley,Joshiawa Paulk,Justin M. Roberts,Amanda Souza,Sirano Dhe‐Paganon,James E. Bradner
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2015-06-19
卷期号:348 (6241): 1376-1381
被引量:1173
标识
DOI:10.1126/science.aab1433
摘要
The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.
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