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lüll Potent Anti-Diabetic Actions of a Novel Non-Agonist PPARgamma Ligand that Blocks Cdk5-Mediated Phosphorylation Kamenecka TM; Busby SA; Kumar N; Choi JH; Banks AS; Vidovic D; Cameron MD; Schurer SC; Mercer BA; Hodder P; Spiegelman BM; Griffin PRProbe Reports from the NIH Molecular Libraries Program-/-ä 2010[]; ä (ä): äThe incidence of diabetes is increasing rapidly as the percentage of the population ages and becomes more obese. According to the National Center for Health Statistics diabetes is now the sixth leading cause of death in the US. The biguanide metformin is typically the first-line medication used for treatment of type 2 diabetes mellitus (T2DM) as safety concerns over the use of the thiazolidinedione class [(TZD); rosiglitazone (Avandia) and pioglitazone (Actos) [1]] of insulin sensitizers has grown. This is unfortunate as TZDs have consistently shown robust efficacy for treatment of T2DM. TZDs target the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) and are classified as full agonists. While weight gain is associated with use of TZDs, the major safety concerns include edema, plasma volume expansion (PVE or hemodilution) which is likely linked to cardiomegaly and increased risk of congestive heart failure, and an increased risk of bone fractures. The latter risk is most troublesome as detection is typically only made when a patient suffers a fracture. Studies in animal models and in clinical trials have shown that indicators of weight gain and PVE, while not eliminated, can be minimized without loss of insulin sensitization by the use of modulators that are weak or partial agonists of PPARgamma (e.g., minimal agonism of the receptor as compared to TZDs). Partial agonists have been referred to as selective PPARgamma modulators or SPPARgammaMs and this class of ligand has been shown to have a different binding mode in the PPARgamma ligand binding pocket (LBP) as compared to the full agonists [2]. Selective recruitment of transcriptional coactivators by partial agonists has also been demonstrated. A combination of different ligand binding mode and distinct coactivator recruitment profile may explain the change in gene expression patterns compared to that of full agonists [3]. While it is unclear if the bone fracture risk has been minimized with use of such agents, these studies clearly demonstrate that the anti-diabetic efficacy of partial agonists is uncoupled from their transcriptional activity but does correlate well with binding potency. Recently we have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Due to their improved adverse event profile of partial agonists and the observation of separate biochemical activities of PPARgamma ligands, we sought to develop compounds with high affinity binding to PPARgamma but that lacked classical agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Here we describe one such compound, ML244, which has a unique mode of binding to PPARgamma, has potent anti-diabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARgamma drugs. Unlike TZDs, ML244 does not interfere with bone formation in culture. These data illustrate that new classes of anti-diabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARgamma.ä |