title: Slow self-activation enhances the potency of viridin prodrugs.
abstract: When the viridin wortmannin (Wm) is modified by reaction with certain nucleophiles at the C20 position, the compounds obtained exhibit an improved antiproliferative activity even though a covalent reaction between C20 and a lysine in the active site of PI3 kinase is essential to Wm's ability to inhibit this enzyme. Here we show that this improved potency results from an intramolecular attack by the C6 hydroxyl group that slowly converts these inactive prodrugs to the active species Wm over the 48 h duration of the antiproliferative assay. Our results provide a guide for selecting Wm-like compounds to maximize kinase inhibition with the variety of protocols used to assess the role of PI3 kinase in biological systems, or for achieving optimal therapeutic effects in vivo . In addition, the slow self-activation of WmC20 derivatives provides a mechanism that can be exploited to obtain kinase inhibitors endowed with physical and pharmacokinetic properties far different from man-made kinase inhibitors because they do not bind to kinase active sites.
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Blois
authors.forename: Hushan
authors.initials: H
authors.lastname: Yuan
authors.forename: Adam
authors.initials: A
authors.lastname: Smith
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pacold
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Lee
authors.initials: L
authors.lastname: Josephson
mesh_terms: D000730:Androstadienes / Q000737:chemistry; D000736:Androstenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001430:Bacteriocins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000736:Androstenes; D001430:Bacteriocins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011355:Prodrugs; D047428:Protein Kinase Inhibitors; D000077191:Wortmannin; C012097:viridin