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.