Obesity and comorbid type 2 diabetes represent a frequent and growing global problem. The insulin resistance syndrome was first described in 1988 and contributes to both conditions and indeed is generally accepted to represent a pathophysiological link between the two. It is estimated that this syndrome affects 70 to 80 million Americans and is characterized by a failure of insulin to stimulate glucose utilization and uptake into tissues. Considerable attention has been paid to the development of molecules able to reduce insulin resistance such as agonists of nuclear hormone receptors, for example, peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs). Indeed the PPAR agonists Rosiglitazone and Pioglitazone are the only drugs on the market that are indicated for insulin resistance. LeadDiscovery has recently published a report overviewing the therapeutic potential of GSK-3 inhibitors (Click here for access). This class of drug stands to play a major role in the treatment of many diseases including diabetes. In addition to improving glucose disposal and possible insulin secretion, GSK-3 inhibitors may increase insulin sensitivity. This latter effect is related to the ability of GSK-3 to phosphorylate serine/threonine residues on IRS-1, which in turn attenuates insulin signaling. On the other hand, insulin receptor tyrosine kinase, phosphorylates multiple IRS-1 tyrosine residues in response to insulin and in contrast to serine/threonine phosphorylation is a positive trigger of insulin action, and hence molecules that activate the insulin receptor beta-subunit tyrosine kinase may, like GSK-3 inhibitors, be of use in the treatment of diabetes. One such molecule is Telik's TLK19780. This non-peptide small molecule has recently been shown to selectively enhance maximal insulin-stimulated insulin receptor autophosphorylation and insulin sensitivity. TLK19780 was shown to be rapid in action enhancing insulin-stimulated glucose transport and both the sensitivity and maximal responsiveness to insulin in adipocytes. These studies therefore support the development of molecules that phosphorylate the insulin receptor and its substrates as alternatives to nuclear hormone receptor agonists for the treatment of type 2 diabetes. An IND is expected to be filed for TLK-19781, another orally-active insulin receptor activator being developed by Telik, in 2003. Telik and their collaborators, Sanwa are jointly seeking a multinational partner for key markets other than Asia and Japan

Entry date November, 2000

Adapted from Pender et al, J Biol Chem 2002 Nov 15;277(46):43565-43571

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