Scientists at UC Irvine have discovered that a synthetic compound originally derived from a sun anemone toxin enhances metabolic activity and shows potential as a treatment for obesity and insulin resistance.
The findings, published online this week in Proceedings of the National Academy of Sciences, present the first evidence that the drug candidate – which in March got positive results in a phase-one safety clinical trial – may work in an anti-obesity capacity.
UC Irvine licensed ShK-186 to Kineta Inc., a Seattle-based biotechnology company, in 2009; it’s the company’s lead drug candidate. Kineta is developing the compound to treat autoimmune diseases, such as multiple sclerosis, psoriatic arthritis and lupus. It has also licensed ShK-186 for the treatment of metabolic syndrome and obesity.
Potassium channels regulate cell membrane activities and control a variety of other cellular processes. ShK-186 selectively blocks the activity of a protein that promotes inflammation through the Kv1.3 potassium channel. Earlier research using mice without a Kv1.3 potassium channel gene suggested that Kv1.3 may regulate body weight and the basal metabolic rate.
In the current study, Dr. George Chandy and colleagues evaluated ShK-186 in tests on obese mice that ate a high-fat, high-sugar diet. They found that the therapy reduced weight, white fat deposits, liver fat, blood cholesterol and blood sugar by activating calorie-burning brown fat, suppressing inflammation of white fat and augmenting liver function. The compound had no effect on mice that ate standard chow.
“This is a new twist in a sustained journey of discovery made over 30 years that charts the course for expeditious translation to humans who suffer from potentially lethal consequences of metabolic syndrome and autoimmune diseases,” said Chandy, a UC Irvine professor of physiology & biophysics and a Kineta scientific adviser.
“Knowing that ShK-186’s unique mechanism of action may have broad applications across multiple therapeutic disciplines, such as autoimmune diseases and now obesity, further adds to the potential of this compound. This study also shows how medical progress can be made through academic and private-sector partnerships,” added Charles Magness, president and CEO of Kineta.
According to the World Health Organization, obesity worldwide has nearly doubled since 1980. In 2008, more than 200 million men and nearly 300 million women, or 11 percent of the global population, were obese. Diabetes is expected to affect about 300 million people by 2030, at an annual cost of $260 billion.
Sanjeev Kumar Upadhyay, Kristin Eckel-Mahan, M. Reza Mirbolooki, Indra Tjong, Galina Schmunk, Briac Halbout, Brian Pedersen, Emiliana Borrelli, Dr. Ping H. Wang, Jogeshwar Mukherjee and Paolo Sassone-Corsi of UC Irvine; Amanda Koehne and Stephen M. Griffey of UC Davis; and Shawn Iadonato of Kineta also contributed to the study, which received support from the National Institutes of Health, a UC Irvine bridge grant and the Ko Family Foundation.