期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 23, 页码 10463-10472出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00975
关键词
-
资金
- Scripps Institution of Oceanography (E. W. Scripps Associates)
- UCSD Academic Senate Research Award [RP42S-HUGHES]
- American Cancer Society Institutional Research Grant (ACS-IRG Grant) [15-172-45]
- Director's New Innovator Award Program NIH [DP2 OD007237]
- National Biomedical Computation Resource (NBCR) through NIH [P41 GM103426]
- NIH [S10 OD0106400]
- NATIONAL CANCER INSTITUTE [R01CA201303] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P41GM103426, R01GM120055] Funding Source: NIH RePORTER
Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3K alpha treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu, corresponding to addition of the inhibitor and elimination of methanol. The binding pose of the inhibitor bound to PI3K alpha was modeled, and hydrogen-deuterium exchange mass spectrometry experiments supported this model. Against a panel of kinases, neolymphostin showed good selectivity for PI3-kinase and mTOR. In addition, the natural product blocked AKT phosphorylation in live cells with an IC50 of similar to 3 nM. Taken together, neolymphostin is the first reported example of a covalent kinase inhibitor from the bacterial domain of life.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据