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: