Yale Researchers ID Target Region in Key Molecule in Duchenne Muscular Dystrophy (DMD); Tyrosine Phosphatase Molecule (MKP5) Previously Thought “Undruggable”—Finding Suggests Possible Treatment Strategy for DMD & Possibly Broader Applications in Fibrosis

Researchers at Yale University have identified a possible treatment for Duchenne muscular dystrophy (DMD), a rare genetic disease for which there is currently no cure or treatment, by targeting an enzyme that had been considered "undruggable." The finding appears in the August 25, 2020 issue of Science Signaling. The article is titled “An Allosteric Site on MKP5 Reveals a Strategy for Small-Molecule Inhibition.” DMD is the most common form of muscular dystrophy, a disease that leads to progressive weakness and eventual loss of the skeletal and heart muscles. It occurs in 16 of 100,000 male births in the U.S. People with the disease exhibit clumsiness and weakness in early childhood and typically need wheelchairs by the time they reach their teens. The average life expectancy is 26. While earlier research had revealed the crucial role played by an enzyme called MKP5 in the development of DMD, making it a promising target for possible treatment, scientists for decades had been unable to disrupt this family of enzymes, known as protein tyrosine phosphatases, at the enzymes' "active" site where chemical reactions occur. In the new study, Anton Bennett, PhD, the Dorys McConnell Duberg Professor of Pharmacology and Professor of Comparative Medicine at the Yale School of Medicine, and his team screened over 162,000 compounds. They identified one molecular compound that blocked the enzyme's activity by binding to a previously undiscovered allosteric site--a spot near the enzyme's active site. "There have been many attempts to design inhibitors for this family of enzymes, but those compounds have failed to produce the right properties," Dr. Bennett said.
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