Slow self-activation enhances the potency of viridin prodrugs.

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Blois J, Yuan H, Smith A, Pacold ME, Weissleder R, Cantley LC, Josephson L

Slow self-activation enhances the potency of viridin prodrugs.

J Med Chem. 2008 Aug 14;51(15):4699-707. doi: 10.1021/jm800374f. Epub 2008 Jul 17.

PubMed ID

18630894 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Wortmannin	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	IC 50 (nM)	17.6	N/A	N/A	Details