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Sep 08, 2011
 |  BC Innovations  |  Cover Story

PPARgamma: none is more

A team from Scripps Florida and the Dana-Farber Cancer Institute has developed peroxisome proliferation-activated receptor-g-binding compounds that have potent antidiabetic activity but do not actually agonize the receptor and thus lack the side effects commonly associated with the target.1 The researchers have founded Adipothermics Inc., with backing from Third Rock Ventures, to advance the new class of compounds into the clinic.

Peroxisome proliferation-activated receptor-g (PPARG; PPARg) agonists marketed to treat type 2 diabetes include GlaxoSmithKline plc's Avandia rosiglitazone and Takeda Pharmaceutical Co. Ltd.'s Actos pioglitazone. The insulin sensitizers posted 2010 sales of $677 million and $4.7 billion, respectively.2

However, both drugs have faced regulatory scrutiny because of safety concerns. Last year, the EMA recommended suspending its approval of Avandia based on a retrospective analysis suggesting the drug increases the rate of heart attacks. This year, Takeda withdrew Actos from the French market after a retrospective analysis indicated the drug may be associated with an increased risk of bladder cancer.

PPARg agonists also cause weight gain, edema and a greater risk of bone fractures, all of which are noted on the drugs' labels.

Last year, the Scripps-Dana-Farber team published in Nature that the insulin-sensitizing effects of Avandia and Actos might not actually be caused by PPARg agonism, but instead may be caused by the compounds' ability to block the phosphorylation of PPARg by cyclin dependent kinase 5 (CDK5).3,4

However, it remained unknown whether it would be possible to pharmacologically block phosphorylation without agonizing PPARg and, if it could be done, whether such a compound would sensitize cells to insulin with a better safety profile than a PPARg agonist.

"The correlation seen in our first paper was strongly suggestive that blocking CDK5...

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