可药性
生物
调节器
转录因子
KEAP1型
突变体
癌细胞
蛋白质组学
细胞生物学
癌症
癌症研究
计算生物学
遗传学
基因
作者
Liron Bar-Peled,Esther K. Kemper,Radu M. Suciu,Ekaterina V. Vinogradova,Keriann M. Backus,Benjamin D. Horning,Thomas A. Paul,Taka-Aki Ichu,Robert Svensson,José Olucha,Max W. Chang,Beverley Kok,Zhou Zhu,Nathan T. Ihle,Melissa M. Dix,Ping Jiang,Matthew M. Hayward,Enrique Sáez,Reuben J. Shaw,Benjamin F. Cravatt
出处
期刊:Cell
[Elsevier]
日期:2017-10-01
卷期号:171 (3): 696-709.e23
被引量:207
标识
DOI:10.1016/j.cell.2017.08.051
摘要
The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.
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