A joint study conducted by the Scripps Research Institute and the Dana-Farber Cancer Institute at Harvard University has discovered a new type of anti-diabetic therapeutic that works by targeting a particular molecular switch.
The findings set the stage for the development of new anti-diabetic therapeutics that will have drastically reduced adverse side effects compared to current anti-diabetics such as Avandia (rosiglitazone), which will be discontinued from sale this fall amid concerns that it increases the risk of heart attack.
The results of the new study were published in the journal Nature. It describes a newly-discovered compound called SR1664 and was led by Patrick R. Griffin with the Department of Molecular Therapeutics at Scripps Florida, Theodore Kamenecka, the associate scientific director of medicinal chemistry at Scripps Florid, and Bruce Spiegelman, a professor of cell biology at Dana-Farber Cancer Institute.
“In this study, we demonstrate that we have discovered novel compounds that work effectively through a unique mechanism of action on a well-validated clinical target for diabetes,” stated Griffin. “This unique mechanism of action appears to significantly limit side effects associated with marketed drugs. This study is a great example of interdisciplinary, inter-institutional collaboration with chemistry, biochemistry, structural biology, and pharmacology.”
“It appears that we may have an opportunity to develop entire new classes of drugs for diabetes and perhaps other metabolic disorders,” says Spiegelman.
The study is a follow-up on research that the authors published last year in the same journal, Nature. That research suggested that the development of insulin resistance in humans could be caused by a mechanism linked to obesity. The research found that a protein called PPARG affects the normal function of several genes when it undergoes phosphorylation, or the addition of a phosphate group to the protein. The kinase Cdk5, an enzyme involved in multiple sensory pathways, is responsible for causing the phosphorylation of PPARG.
The researchers’ new study confirms what they suspected in their original research: blocking Cdk5 from acting on PPARG could be the basis of effective anti-diabetes therapies. The SR1664 compound discovered in the newer research binds to PPARG but does not activate the transcription of genes.
Griffin’s team is cautious about being overly optimistic in their report on the side effects of anti-diabetes treatment with SR1664. However, the research did clearly demonstrate that this type of treatment causes fewer side effects in mice than medications such as Avandia, which can cause weight gain or increased plasma volume.
In the study, the researchers treated diabetic mice with both Avandia and with SR1664. While both groups showed improved blood glucose levels, the mice treated with Avandia also displayed more fluid retention and weight gain soon after beginning treatment. The mice treated with SR1664, on the other hand, showed neither. The researchers also tested SR1664 in cell cultures for its effect on bone formation and fat generation in bone cells, both side effects of Avandia and other therapies. SR1664 caused no such side effects.
Although SR1664 will likely not be used directly as a drug, its discovery will allow researchers to develop similar compounds that can be used to treat diabetes. “With data in hand showing that our compounds are as efficacious as the currently marketed PPARG modulators, while demonstrating a significant improvement of side effects in limited studies, we are now advancing newer compounds with improved pharmaceutical properties into additional studies,” says Griffin.
