New compound shows promise for safe, effective treatment of heart attack and stroke
Heart attack and ischemic stroke affect hundreds of thousands of Americans every year and are leading causes of death in the United States. Both of these conditions are caused by blood clots that block vessels and interrupt blood flow to the heart or the brain, respectively. Antiplatelet therapies such as aspirin prevent clotting by decreasing the activity of blood cells called platelets, thereby lowering the risk of dying from a heart attack or having a stroke. But these drugs can cause serious side effects, such as gastrointestinal toxicity, abnormally low blood cell counts, and bleeding. Therefore, there is a strong need for research aimed at better understanding the molecular mechanisms leading to platelet activation in order to develop improved therapies.
Toward that goal, Sanford-Burnham researchers recently discovered a key role for a protein called dual-specificity phosphatase 3 (DUSP3) in platelet signaling and the formation of blood clots. As reported recently in the journal Circulation, the researchers developed a novel DUSP3 inhibitor that decreases the aggregation of human platelets. The findings pave the way for the development of effective drugs for the treatment of blood clotting in heart attack and ischemic stroke in humans.
“There is a pressing medical need for novel antiplatelet agents with a more favorable safety profile and less patient resistance,” said study co-corresponding author Lutz Tautz, Ph.D., research assistant professor in the Cell Death and Survival Networks Program at Sanford-Burnham. “Our findings provide proof-of-principle for a novel and potentially safer DUSP3-based antiplatelet therapy for the treatment of arterial thrombosis.”
Safe and effective
DUSP3 is a member of a family of molecules called protein tyrosine phosphatases (PTPs), which are expressed in platelets but whose role in platelet activation was largely unknown. In addition, DUSP3 has been implicated in cancer, but some data suggested this protein causes tumors while other studies showed a tumor suppressive effect. While searching for the biological functions of DUSP3, a team led by Souad Rahmouni, Ph.D., who is a research associate at the University of Liège in Belgium and was formerly a postdoctoral fellow associate at Sanford-Burnham, discovered that this protein is highly expressed in human and mouse platelets. To further investigate the role of DUSP3 in platelets, Rahmouni teamed up with Cécile Oury, Ph.D, an expert in platelet biology at the University of Liège, as well as Tautz and other researchers at Sanford-Burnham.
In the new study, the researchers found that platelet aggregation was inhibited in genetically modified mice that were deficient in DUSP3. Whereas injection of a mixture of collagen and epinephrine fully occluded blood vessels in normal mice, DUSP3-deficient mice showed no evidence of vessel occlusion due to blood clots. Moreover, DUSP3 deficiency did not cause excessive bleeding in these mice, suggesting that drugs targeting this protein could be safer than existing antiplatelet therapies.
With the goal of identifying promising DUSP3 inhibitors, the researchers screened hundreds of thousands of drug-like molecules in a chemical library and tested the four most potent compounds in human platelets. One of these compounds in particular showed excellent selectivity for DUSP3 and inhibited the aggregation of human platelets.
“This is the first time a PTP implicated in platelet signaling has been targeted with a small-molecule drug,” said Tautz, a chemical biologist who has transformed conventional drug discovery strategies to develop potent and selective small-molecule PTP inhibitors for the treatment of diseases ranging from cancer and autoimmune disorders to Alzheimer’s disease and schizophrenia. “Previously reported DUSP3 inhibitors suffer from either poor selectivity, lack of efficacy, or both, or cause immediate spontaneous aggregation of platelets. The novel DUSP3 inhibitor we developed could serve as the basis for the development of safer, more effective drugs for the treatment of heart attack and ischemic stroke.”
Moving forward, the researchers will test whether the new DUSP3 inhibitor or a chemically optimized version of the compound reduces blood clotting in mice. “Success in this endeavor will further validate DUSP3 as a compelling new drug target in arterial thrombosis. Efficacious compounds may also directly enter preclinical studies, paving the way for clinical trials in humans.”
Link to the paper directly at: http://circ.ahajournals.org/content/131/7/656.full?sid=77ff7c91-397c-441f-ba19-69d36d61e217
Janelle Weaver, Ph.D., a freelance writer, contributed to this article.