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J Med Chem. 2018 Dec 13;61(23):10463-10472. doi: 10.1021/acs.jmedchem.8b00975. Epub 2018 Nov 28.

Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

Author information

1
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography , University of California, San Diego , La Jolla , California 92093 , United States.
2
Department of Chemistry and Biochemistry , University of California, San Diego , La Jolla , California 92093 , United States.
3
Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.
4
School of Medicine , University of California, San Diego , La Jolla , California , 92093 , United States.

Abstract

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 PI3Kα 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 PI3Kα 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 ∼3 nM. Taken together, neolymphostin is the first reported example of a covalent kinase inhibitor from the bacterial domain of life.

PMID:
30380865
PMCID:
PMC6688905
[Available on 2019-12-13]
DOI:
10.1021/acs.jmedchem.8b00975
[Indexed for MEDLINE]

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