02:28am Sunday 20 August 2017

Scripps Florida Scientists Establish that Drug Candidates Can Block Pathway Associated with Cell Death in Parkinson’s Disease

The studies, published in the Journal of Medicinal Chemistry and Scientific Reports, suggest that it is possible to design highly effective and highly selective (targeted) drug candidates that can protect the function of mitochondria, which provide the cell with energy, ultimately preventing brain cell death.

These drug candidates act on what are known as the JNK (pronounced “junk”) kinases—JNK1, JNK2 and JNK3—each an enzyme with a unique biological function. JNK is linked to many of the hallmark components of Parkinson’s disease, such as oxidative stress and programmed cell death.

“These are the first isoform selective JNK 2/3 inhibitors that can penetrate the brain and the first shown to be active in functional cell-based tests that measure mitochondrial dysfunction,” said Philip LoGrasso, a TSRI professor who led both studies. “In terms of their potential use as therapeutics, they’ve been optimized in every way but one—their oral bioavailability. That’s what we’re working on now.”

The new studies raise the hope that such a therapy could prevent the gradual degeneration of brain cells in Parkinson’s disease and halt these patients’ decline.

“Some of these compounds had a level of selectivity that ranged as high as 20,000-fold against competing targets and were extremely effective against oxidative stress and mitochondrial dysfunction—both potent cell killers,” added HaJeung Park, director of Scripps Florida’s X-ray Crystallography Core Facility and the first author of the Scientific Reports study.

The scientists found that within JNK3, a single amino acid—L144—was primarily responsible for the high level of JNK3 selectivity. Isoform selectivity can help to limit potential side effects of a drug.

Intriguingly, some recent studies have shown that JNK3 not only plays a central role in brain cell death in Parkinson’s disease, but also in Alzheimer’s disease. LoGrasso and his colleagues also believe their JNK3 drug candidates have potential for treating ALS (Lou Gehrig’s disease).

In addition to LoGrasso and Park, authors of the Scientific Reports study, “Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles,” include Sarah Iqbal, Pamela Hernandez, Rudy Mora, Ke Zheng and Yangbo Feng of TSRI. See http://www.nature.com/srep/index.html

The first author of the Journal of Medicinal Chemistry study, “Design and Synthesis of Highly Potent and Isoform Selective JNK32 Inhibitors: SAR Studies on Aminopyrazole Derivatives,” is Ke Zheng of TSRI. Other authors include Sarah Iqbal, Pamela Hernandez, HaJeung Park and Yangbo Feng of TSRI. See http://pubs.acs.org/doi/abs/10.1021/jm501256y

Both studies were supported by the Department of Defense (W81XWH-12-1-0431 1192) and the National Institutes of Health (GM103825).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.


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