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The Leukemia & Lymphoma Society has awarded a $971,484 Screen to Lead grant to University of North Carolina Lineberger Comprehensive Cancer Center researchers to launch an investigation of new drug compounds that would block enzymes that can become hyperactive in blood cancer cells when mutated.

UNC Lineberger’s John Sondek, PhD, (right), with Nicole Hajicek, PhD, research assistant professor.

UNC Lineberger’s John Sondek, PhD, a professor in the UNC School of Medicine Departments of Pharmacology and Biochemistry & Biophysics, and his team will use the funding to search for potential inhibitors of two enzymes that can be mutated in lymphoma and leukemia.

Sondek developed the project with UNC Lineberger’s Qisheng Zhang, PhD, associate professor in the UNC Eshelman School of Pharmacy and UNC School of Medicine Department of Pharmacology, and UNC Lineberger’s Ken Pearce, PhD, research professor in the UNC Eshelman School of Pharmacy.

“The Screen to Lead resources provide us with the freedom to work in drug discovery — an area that is normally outside of our focus of basic research,” Sondek said. “With this funding, we are searching for compounds to keep a protein, PLC-gamma1, from becoming aberrantly activated in blood cancer.”

Two closely related phospholipase C gamma enzymes are often mutated in blood cancers, Sondek said. A previous study found that a gene for PLCG1 is mutated in approximately 36 percent in adult T-cell leukemia and lymphomas. When these enzymes become mutated, these proteins are always “on,” and can promote cancer growth, Sondek said. He and his colleagues have mapped the structure of these two enzymes in order to understand their activity when they’re always “on.” In addition, they developed a way to monitor the activity of these enzymes using fluorescent materials.

In their new study, they are planning to screen a group of compounds to determine if any of them can block activity of the two enzymes when they’re mutated.

“Our drug discovery effort will benefit enormously from our success in determining the first atomic-resolution structure of a full-length PLC-gamma isozyme,” he said. “This structure is crucial for understanding how hit compounds interact with PLC-gamma isozymes so that the compounds can be effectively progressed with hit-to-lead, structure-guided medicinal chemistry program.”

Since its founding 70 years ago, LLS, a nonprofit dedicated to blood cancer research and patient services, has invested nearly $1.3 billion in cancer research. LLC announced recently that it was investing $44 million in new grants targeting all the blood cancers – leukemia, lymphoma, myeloma and other rare blood cancers – that impact both children and adults. In all, LLS reported that it is now funding more than 292 research projects around the world for a total investment of $179 million.