Coronavirus Information for the UC San Diego Community

Our leaders are working closely with federal and state officials to ensure your ongoing safety at the university. Stay up to date with the latest developments. Learn more.

Neolymphostin A Is a covalent phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor that employs an unusual electrophilic vinylogous ester

TitleNeolymphostin A Is a covalent phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor that employs an unusual electrophilic vinylogous ester
Publication TypeJournal Article
Year of Publication2018
AuthorsCastro-Falcon G., Seiler G.S, Demir O., Rathinaswamy M.K, Hamelin D., Hoffmann R.M, Makowski S.L, Letzel A.C, Field S.J, Burke J.E, Amaro R.E, Hughes CC
JournalJournal of Medicinal Chemistry
Volume61
Pagination10463-10472
Date Published2018/12
Type of ArticleArticle
ISBN Number0022-2623
Accession NumberWOS:000453488200008
Keywordsassay interference; conserved lysine; immunosuppressant; irreversible inhibitors; lymphostin lk6-a; natural-products; Pharmacology & Pharmacy; phosphatidylinositol 3-kinase; protein-kinases; streptomyces sp ky11783; wortmannin
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 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.

DOI10.1021/acs.jmedchem.8b00975
Short TitleJ. Med. Chem.
Student Publication: 
No
Research Topics: