RT Journal Article
SR Electronic
T1 Oxidation of Protein Tyrosine Phosphatases as a Pharmaceutical Mechanism of Action: A Study Using 4-Hydroxy-3,3-dimethyl-2<em>H</em>-benzo[<em>g</em>]indole-2,5(3<em>H</em>)-dione
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 711
OP 719
DO 10.1124/jpet.103.062745
VO 309
IS 2
A1 Charlotta Liljebris
A1 Pawel Baranczewski
A1 Eva Björkstrand
A1 Styrbjörn Byström
A1 Bo Lundgren
A1 Agneta Tjernberg
A1 Malin Warolén
A1 Stephen R. James
YR 2004
UL http://jpet.aspetjournals.org/content/309/2/711.abstract
AB Growth factor and insulin signal transduction comprise series of protein kinases and protein phosphatases whose combined activities serve to propagate the growth factor signal in a regulated fashion. It was shown previously that such signaling cascades generate hydrogen peroxide inside cells. Recent work has implied that one function of this might be to enhance the feed-forward signal through the reversible oxidation and inhibition of protein tyrosine phosphatases (PTPs). We identified compound 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione (BVT.948) as an agent that is able to inhibit PTP activity in vitro noncompetitively, a mechanism involving oxidation of the catalytic cysteine residue. We investigated the pharmaceutical utility of this compound by examining its effects in a series of in vitro cellular and in vivo assays. Results showed that BVT.948 was able to enhance insulin signaling in cells, although it did not increase tyrosine phosphorylation globally. Furthermore, the compound was active in vivo, enhancing insulin tolerance tests in ob/ob mice, therefore apparently enhancing insulin sensitivity. BVT.948 was able to inhibit several other PTPs tested and also was efficient at inhibiting several cytochrome P450 (P450) isoforms in vitro. The data suggest that inhibitors of PTPs that display noncompetitive kinetics must be viewed with caution because they may oxidize the enzyme irreversibly. Furthermore, although such compounds display interesting biological effects in vitro and in vivo, their general pharmaceutical utility may be limited due to undesired effects on P450 enzymes. The American Society for Pharmacology and Experimental Therapeutics