Drugging the undruggable: Treatment path for muscular dystrophy

Date:
September 11, 2020
Source:
Yale University
Summary:
Researchers 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.'


FULL STORY ========================================================================== Researchers at Yale 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 Aug. 25 edition of
Science Signaling.


==========================================================================
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, the Dorys McConnell Duberg Professor
of Pharmacology and professor of comparative 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," Bennett said.

"Until now, the family of enzymes has been considered 'undruggable.'"
By targeting the allosteric site of MKP5 instead, he said, "We discovered
an excellent starting point for drug development that circumvented the
earlier problems." The researchers tested their compound in muscle
cells and found that it successfully inhibited MKP5 activity, suggesting
a promising new therapeutic strategy for treating DMD.

The research was supported by a National Institutes of Health grant
through the National Institute of Arthritis and Musculoskeletal and
Skin Diseases, as well as by the Blavatnik Fund for Innovation at Yale,
which annually presents awards to support the most promising life science discoveries from Yale faculty.

Bennett said that the Blavatnik funding, which is administered by the
Yale Office of Cooperative Research, was critical in moving the research forward.

"It resulted in a license with a major pharmaceutical company," he said,
"and we hope they will rapidly move forward with the development of
the new treatment." The finding has implications well beyond muscular dystrophy, he added. The researchers have demonstrated that the MKP5
enzyme is broadly implicated in fibrosis, or the buildup of scar tissue,
a condition that contributes to nearly one-third of natural deaths
worldwide.

"Fibrosis is involved in the end-stage death of many tissues, including
liver, lung, and muscle," Bennett said. "We believe this enzyme could be
a target more broadly for fibrotic tissue disease." The research team
from Yale included Naftali Kaminski, the Boehringer-Ingelheim Professor
of Internal Medicine and chief of pulmonary, critical care and sleep
medicine; Jonathan Ellman, the Eugene Higgins Professor of Chemistry and professor of pharmacology; Karen Anderson, professor of pharmacology
and of molecular biophysics and biochemistry; Elias Lolis, professor
of pharmacology; Zachary Gannam, a graduate student in pharmacology;
Kisuk Min, a postdoctoral fellow; Shanelle Shillingford, a graduate
student in chemistry; Lei Zhang, a research associate in pharmacology;
and the Yale Center for Molecular Discovery.


========================================================================== Story Source: Materials provided by Yale_University. Original written
by Brita Belli. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Zachary T. K. Gannam, Kisuk Min, Shanelle R. Shillingford,
Lei Zhang,
James Herrington, Laura Abriola, Peter C. Gareiss, Georgios
Pantouris, Argyrios Tzouvelekis, Naftali Kaminski, Xinbo Zhang, Jun
Yu, Haya Jamali, Jonathan A. Ellman, Elias Lolis, Karen S. Anderson,
Anton M. Bennett. An allosteric site on MKP5 reveals a strategy
for small-molecule inhibition.

Science Signaling, 2020; 13 (646): eaba3043 DOI: 10.1126/
scisignal.aba3043 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200911141747.htm

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