Diabetes therapeutics market. Courtesy: http://marketpublishers.com/lists/8746/news.html
 

The new study, led by Patrick R. Griffin (left), professor and chair of the Department of Molecular Therapeutics at Scripps Florida, Bruce Spiegelman, (centre)  professor of cell biology at the Dana-Farber Cancer Institute, and Theodore Kamenecka(right)  associate scientific director of medicinal chemistry at Scripps Florida, was published September 4, 2011 in the journal Nature. The study describes a new compound known as SR1664.

The finding paves the way for the development of anti-diabetic therapeutics with minimal adverse side effects plaguing currently available drugs such as Avandia (rosiglitazone), scheduled to be removed from pharmacy shelves this autumn due to concerns about increased risk of heart attack.

“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,” said 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."

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“It appears that we may have an opportunity to develop entire new classes of drugs for diabetes and perhaps other metabolic disorders," said Spiegelman. 

Diabetes affects nearly 24 million children and adults in the United States, according to the America Diabetes Association.

 

A Viable Therapeutic Target


The study follows previous research by the authors published last year in Nature that suggested an obesity-linked mechanism that may be involved in the development of insulin-resistance. In that research, the team found disruptions in various genes when a protein known as PPARγ undergoes phosphorylation (when a phosphate group is added to a protein) by the kinase Cdk5, an enzyme involved in a number of important sensory pathways.



The new study confirms that blockage of Cdk5’s action on PPARG is a viable therapeutic approach for development of anti-diabetic agents. The new SR1664 compound is a potent binder to the nuclear receptor PPARG, but does not activate gene transcription via the receptor’s normal mechanism.



While Griffin stressed the difficulty of fully assessing side effects of new compounds such as SR1664, the new research is extremely positive in that it clearly demonstrated fewer of the major well-documented side effects, such as weight gain or increased plasma volume, from SR1664 as compared to Avandia in diabetic mice. 



While both the mice treated with Avandia and those treated with SR1664 demonstrated improved blood sugar levels, those treated with Avandia showed weight gain and increased fluid retention within a few days of beginning treatment; those being treated with SR1664 showed none of these side effects. In cell culture studies, SR1664 also appeared to have little effect on bone formation, nor did it increase fat generation in bone cells, another side effect of current therapies such as Avandia.

While S1664 likely will not be developed as a drug, it now serves as a molecular scaffolding for creation of similar compounds with potential 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,” Griffin said.

LINKS TO LEUKEMIA
An international team of researchers has found a group of mutations involved in T-cell acute lymphoblastic leukemia (T-ALL), and showed that a group of certain drugs, already in clinical use to treat other diseases, can eliminate the cells carrying these mutations in Nature Genetics and may promote the development of novel therapeutic approaches against leukemia. 

The study was led by researcher (L2R) João T. Barata at Instituto de Medicina Molecular in Lisbon, Portugal, jointly with J. Andres Yunes at Centro Infantil Boldrini in Campinas, São Paulo, Brazil, in collaboration with researchers from the National Cancer Institute in Frederick, Maryland, USA, the Erasmus Medical Center, Rotterdam, The Netherlands; and other laboratories in Europe and the US. This is a basic research study with potential clinical impact, was based in part using  samples from pediatric leukemia patients.

T-ALL mostly affects children. It is a blood cancer consisting in an uncontrolled growth in the number of T-lymphocytes (white blood cells from the immune system). The onset of the disease can be triggered by different genetic mutations in genes involved in the proliferation and differentiation of T-cells.

The identification and study of mutations found in leukemia patients is particularly important to help develop more efficient and targeted therapies. Researchers now finds a group of mutations that affect 9% of the patients with T-ALL and may be originating leukemia in these patients.

Most important, researchers demonstrated that a set of pharmaceutical drugs can eliminate the effect of these mutations, unraveling a potential therapeutic application for their discovery.

The current study shows that the mutations occur at the gene coding for a protein localized at the surface of T-cells, the interleukin-7 receptor (IL7R). This protein contacts with both the exterior and the interior of the cells, acting as a bridge to transfer chemical information from the outside to the inside of cells. Information transfer occurs upon the binding of a bloodstream protein (interleukin-7) to the receptor, which triggers a cascade of cellular reactions that are essential for the correct development and proliferation of T-cells.

In the new study, researchers also found that the mutations promote non-stop, uncontrolled T-cell proliferation, independently of extracellular triggers. This capacity to induce cells to grow relentlessly is associated with the ability to originate tumors.

To help fighting the tumors that contain IL7R mutations, the team of researchers studied pharmaceutical drugs  known to act in several steps of the referred cascade of cellular reactions and found that these drugs - which are already being tested against other diseases such as rheumatoid arthritis – can stop cell proliferation induced in mutated cells and promote the elimination of these cells.

Says João T. Barata: “We discovered that the interleukin-7 receptor, which is essential for proper T-cell development, may also have a “dark side”, acting as a Mr. Hyde of sorts. In particular, we found that certain mutations in this gene are involved in pediatric T-cell acute lymphoblastic leukemia and characterized how they act.

"Our observations allowed us to identify potential therapeutic weapons against these tumors. Although pediatric acute lymphoblastic leukemia is among the success stories in cancer therapy, improvements are still needed. We hope our findings will help further increase the efficacy and selectivity of already existing treatments.”

Says J. Andrés Yunes, from Centro Infantil Boldrini in Campinas, São Paulo, Brazil: “Most mutations found resulted in the insertion of a cystein aminoacid into the IL7R. It is this new cystein that perverts the normal functioning of the receptor by linking two mutant IL7R molecules through disulfide bonds. I’m eager to know what is the probability of having a cystein codon insertion, in this specific location of the gene, to address whether this is random or not.citation”

Says Scott K. Durum, from the National Cancer Institute in Frederick, Maryland, USA: “On the one hand, the IL-7 receptor should have seemed a likely cause of cancer because it normally stimulates cells to grow, which is what cancer cells do.  On the other hand this seemed unlikely because there are normally two chains involved in signaling.  However these remarkable mutations in just one of the chains circumvent the need for the second chain.  In addition to existing drugs that can target this pathway, we aim to develop new antibodies against IL-7 receptor to treat these patients. “

This research was funded by the Portuguese Foundation for Science and Technology (FCT - Fundação Portuguesa para a Ciência e a Tecnologia), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and the intramural program of the National Cancer Institute, NIH.