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Nov 1, 2009 (Vol. 29, No. 19)

Search Intensifies for Diabetes Drugs

Myriad of Compounds Intended to Stop the Progression of Metabolic Diseases Moves Through the Pipeline

  • Click Image To Enlarge +
    The SIRT1 enzyme is the most well-studied of the seven sirtuin family members. (David Shopper Photography)

    The competition to develop new therapeutics targeting metabolic disease is heating up. Here’s why: the latest estimates from the American Diabetes Association state that there are nearly 24 million Americans with diabetes. In addition, approximately 32% of American adults are medically obese.

    Many companies have honed in on this large and growing market, and several of them presented their latest findings at IQPC’s “Groundbreaking Advances and Key Opinions in Metabolic Diseases Drug Discovery and Development” held recently in San Francisco.

    “When we founded the company, we wanted to work on the biology responsible for disease progression,” stated Teo Uysal, president and CEO of Syndexa Pharmaceuticals. The company is now focused on endoplasmic reticulum (ER) stress and inflammatory pathways. Uysal said there is growing evidence that ER functional capacity is important in disease progression. If its capacity or homeostasis is compromised, the related pathways eventually have a negative effect on insulin signaling in peripheral tissues and macrophage function.

    “ER, in its functional capacity, appears to be at a very critical junction in biology. Its modulation seems to have a therapeutic benefit in multiple indications,” explained Uysal. Animal studies support this concept. If one can alleviate the cell stress, he added, one will observe profound antidiabetic and antiatherosclerotic effects.

    The company has developed technologies to study this organelle, some of which are partially licensed from its scientific founder’s lab (Gokhan Hotamisligil, M.D., Ph.D.) at Harvard University. Using systems biology drug-screening capabilities, the company has been able to monitor the adaptive functional capacity of ER, with the goal of identifying small molecules to enhance this function.

    Syndexa is also researching a stress kinase, JNK (c-Jun-N-terminal), which plays a critical role in type 2 diabetes, as well as other metabolic diseases. The company’s approach is unique, according to Uysal, because it has chosen to use allosteric inhibition of the kinase by targeting the substrate-docking site, instead of the ATP binding site, thereby avoiding problems like cross-reactivity.

  • Modified Lipid Biosynthesis

    Click Image To Enlarge +
    Activation of the overlapping metabolic and inflammatory signaling pathways causes an increase in ER stress and JNK activity.

    Researchers at Xenon Pharmaceuticals are developing inhibitors of SCD1 (Strearoyl coA Desaturase), the rate-limiting enzyme for production of mono-unsaturated fatty acids. “SCD1 is an interesting drug target because it seems to be at a junction point of how the body regulates whether or not lipids go into a storage or oxidation pathway,” explained Michael Winther, Ph.D., senior director, drug discovery. “That choice, that’s made in different tissues at different times, is fundamental to metabolic health and regulation of weight and fatty acid levels.”

    The company has moved forward with studies because it has human data supporting the extrapolation of the rodent pathways. Rodents with SCD1 knock-out have a changed fatty acid composition that’s easy to measure. However, there is no known SCD1 knock-out in humans.

    This presented its own challenges as there were no precedent in vitro or in vivo assays available. “The first challenge was HTS—there were no known small molecule inhibitors to inhibit SCD1 in the way we wanted our drug to inhibit it.” In addition, there was no crystallographic structure for the SCD1 enzyme, so computer-assisted drug design was of limited value. So, the researchers developed an HTS method for SCD1, which is also useful for screening related enzymes involved in fatty-acid metabolism, specifically other fatty-acid desaturase and fatty-acid elongase enzymes.

    Another challenge in developing the model for SCD1 is the rodent models. Rodents have four SCD1 genes (SCD1, 2, 3, and 4), versus humans, which have SCD1 and SCD5. So rodent studies have to be treated with caution since one cannot replicate the SCD1 population that exists in humans. “If you knock out certain lipid pathways, you’re going to have the potential to run into problems. This is true for any lipid pathway targets, because they are essential for maintenance of health,” added Dr. Winther.

    His group will continue its work on the basic biology of SCD1 and how it regulates the process in rodents, and then extend that information into humans. “A better understanding of how SCD1 regulates body weight and metabolism is the next stage for the field.”

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