Update: How the pharmaceutical/biotechnology industry might develop better insulin sensitizers

 

PPARγ

This article is an update of a three-part series on insulin sensitizers for treatment of type 2 diabetes that was published on this blog in August and September of 2010.

Summary of our August/September 2010 blog articles on insulin sensitizers

In part 1 of the series (posted August 23, 2010), we focused on safety issues with the two marketed thiazolidinedione (TZD) peroxisome proliferator-activated receptor gamma (PPARγ) agonists–rosiglitazone (GlaxoSmithKline’s Avandia) and pioglitazone (Takeda’s Actos). Both of these insulin sensitizing, antidiabetic agents induce weight gain, and carry an increased risk of edema and heart failure. In addition, rosiglitazone carries an increased risk of myocardial infarction. On September 23, 2010, the FDA restricted access to Avandia, and the European Medicines Agency (EMA) recommended that the drug be pulled from the market.

In part 2 of the series (posted on August 29, 2010), we discussed a breakthrough discovery by Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and his colleagues, published in the 22 July 2010 issue of Nature. It was the Spiegelman group that originally identified PPARγ as the master regulator of adipocyte biology and differentiation, which eventual led to the development of the TZD drugs.

In that research, the Spiegelman group found evidence that the insulin sensitizing and antidiabetic effects of PPARγ agonists may not be due to the agonistic effects of these compounds on PPARγ, but to their ability to inhibit phosphorylation (at Ser 273) of PPARγ by the enzyme cyclin-dependent kinase 5 (CDK5). A weak PPARγ agonist, the benzoyl 2-methyl indole (non-TZD) MRL24, inhibits CDK5 phosphorylation of PPARγ as well as rosiglitazone, and also has very good antidiabetic activity.

CDK5 phosphorylation of PPARγ does not change the ability of PPARγ to upregulate transcription of genes involved in adipocyte differentiation. However, it inhibits the ability of PPARγ to upregulate transcription of a set of genes, including the gene for the adipokine adiponectin, that induce insulin sensitivity and resistance to obesity. Although both rosiglitazone and MRL24 inhibit CDK5 phosphorylation of PPARγ, treatment with the strong agonist rosiglitazone results in upregulation of both the adipogenic and the pro-insulin resistance sets of genes, while treatment with MRL24 results only in upregulation of the pro-insulin resistance set.

Researchers hypothesize that it is the upregulation of the adipogenic gene set that is responsible for the adverse effects of strong agonists of PPARγ–weight gain, edema, and the risk of heart failure. In contrast, the upregulation of adiponectin and the other members of the pro-insulin resistance gene set is thought to be responsible for the desirable, antidiabetic effect of PPARγ agonists.

In part 3 of the series (published on September 16, 2010), we discussed two essays, also published in the 22 July 2010 issue of Nature, that discuss using the new breakthrough results of the Spiegelman group to discover and develop improved insulin sensitizers. These essays recommended that researchers screen for compounds that inhibit CDK5 phosporylation of PPARγ rather than those that are strong PPARγ agonists. We also discussed the prospects for early-stage non-TZD partial or selective agonists of PPARγ, which might constitute second-generation insulin sensitizers.

New research from the Spiegelman group based on their 2010 breakthrough result

On September 4, 2011, Nature published, as an “advance online publication”, a new paper [subsequently published in Nature’s 22 September 2011 print edition] by Bruce Spiegelman, Patrick R. Griffin and Theodore Kamenecka (Scripps Research Institute, Jupiter, Florida) and their colleagues on discovery of novel compounds that bind to PPARγ and block its phosphorylation by CDK5, and which completely lack PPARγ agonist activity. (These compounds are thus neither full nor partial/selective agonists of PPARγ.)

One of these compounds, SR1664, exhibited potent antidiabetic and insulin sensitizing activity in two mouse models of obesity-associated type 2 diabetes. However, unlike full agonists such as rosiglitazone, it did not cause fluid retention and weight gain in these animal models. Fluid retention and weight gain are major adverse effects of TZDs in their own right, and are also thought to be related to the even more serious cardiovascular adverse effects of TZDs. Moreover, SR1664 did not interfere with bone mineralization in cultured osteoblasts; this assay is a model for the loss of bone mineral density and increase risk of fracture seen with TZDs.

The researchers developed SR1664 by starting with a partial agonist of PPARγ developed by GlaxoSmithKline, known as compound 7b. Using compound 7b as a scaffold for chemical modification, the researchers optimized for (1) high binding affinity for PPARγ, (2) blocking of CDK5-mediated PPARγ phosphorylation and (3) lacking classical agonism. The structure of two resulting compounds, SR1664 and SR1824, are given in the new Spiegelman/Griffin paper.

Although the new study suggests that SR1664 may be as efficacious an insulin sensitizer as TZDs without inducing their major adverse effects, the safety of these compounds in humans (as opposed to the mouse models) remains unproven. Moreover, SR1664 has unfavorable pharmacokinetic properties and is thus not a good candidate for development as a drug. According to a press release, Dr. Griffin’s molecular therapeutics group and Dr. Kamenecka’s medicinal chemistry group at Scripps have been using S1664 as a molecular scaffold for the discovery of derivatives with improved pharmacokinetic properties. They are advancing such newer compounds into additional studies.

Why develop new insulin sensitizers rather than depending on current antidiabetic drugs?

In Heidi Ledford’s commentary published in the 22 July 2010 issue of Nature, the author points out that some observers believe that pharmaceutical companies will be reluctant to attempt to develop new insulin sensitizers that target PPARγ, given the checkered history of that class of drugs. And other medical authorities believe that the older, inexpensive, and well proven type 2 diabetes drugs–insulin, metformin, and sulfonylureas–are adequate for the treatment of type 2 diabetes.

However, there remain important unmet needs in the treatment of type 2 diabetes. These especially include dealing with the relentlessly progressive nature of type 2 diabetes–for example, even patients who initially succeed in reaching glycemic goals with only diet/exercise and metformin will eventually need multidrug treatment, including insulin. Progression of type 2 diabetes is mainly due to the loss of pancreatic beta-cell function, which results in increased impairment of a patient’s ability to produce insulin in response to increased blood glucose.

Despite the major safety issues with TZDs, there is both animal model and human evidence that these agents may work to preserve and/or enhance beta-cell function. It will be important to determine if nonagonist second-generation insulin sensitizer candidates, such as those being developed by the Spiegelman and Griffin groups, also have the beta-cell preserving or enhancing effects of TZDs.

The Harvard/Scripps efforts to discover safer insulin sensitizers illustrate the potential role of academia (based on breakthrough science) in areas of drug discovery and development that industry is reluctant to undertake. However, although these academic groups might potentially take the nonagonist insulin sensitizers through lead optimization and preclinical studies, eventually industry (whether a biotech company or a pharmaceutical company) will need to take the compounds through clinical trials in order for any drugs to reach the market.
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