期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 142, 期 11, 页码 4960-4964出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.9b10377
关键词
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资金
- Ono Pharma Foundation
- Pfizer
- NIH NIGMS [R35 GM122481]
- NIH NCI [F31CA214028]
- China Scholarship Council [201409110014]
- Advanced Light Source beamline [8.3.1]
Eukaryotic translation initiation factor 4E (eIF4E) binds the m7GTP cap structure at the 5'-end of mRNAs, stimulating the translation of proteins implicated in cancer cell growth and metastasis. eIF4E is a notoriously challenging target, and most of the reported inhibitors are negatively charged guanine analogues with negligible cell permeability. To overcome these challenges, we envisioned a covalent targeting strategy. As there are no cysteines near the eIF4E cap binding site, we developed a covalent docking approach focused on lysine. Taking advantage of a make-on-demand virtual library, we used covalent docking to identify arylsulfonyl fluorides that target a noncatalytic lysine (Lys162) in eIF4E. Guided by cocrystal structures, we elaborated arylsulfonyl fluoride 2 to 12, which to our knowledge is the first covalent eIF4E inhibitor with cellular activity. In addition to providing a new tool for acutely inactivating eIF4E in cells, our computational approach may offer a general strategy for developing selective lysine-targeted covalent ligands.
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