Protein tyrosine phosphatases (PTPs) as drug targets: inhibitors of PTP-1B for the treatment of diabetes.
The phosphorylation of key proteins on tyrosine residues is an important part of many different intracellular signaling cascade mechanisms triggered by hormones and other agents. The deactivation of such signaling processes is catalyzed by protein-tyrosine phosphatases (PTPs), and therefore inhibition of these enzymes is being explored in different indications as a means whereby signaling may be prolonged or even initiated in the absence of the triggering agent. In the case of the signaling cascade initiated by the activation of the insulin receptor, an important gene knockout study in mice has identified PTP-1B as a potential target for anti-diabetes therapy, and has thus made it a focus of attention for several groups. Recent advances in the structure-based design of potent and selective inhibitors of this enzyme are described, as well as some preliminary data for such inhibitors in animal models which, together with more recently published data from further studies on PTP-1B knockout mice and from antisense studies, illustrate the potential of this approach for the treatment of both Type I and Type II diabetes.
Møller
N P
NP
Signal Transduction, Novo Nordisk, Novo Alle, DK-2880 Bagsveerd, Denmark. nphm@novo.dk
Iversen
L F
LF
Andersen
H S
HS
McCormack
J G
JG