Compound Kills Cells of Common Form of non-Hodgkin’s Lymphoma

Small molecule discovered by the SOP’s Computer-Aided Drug Design Center has the potential to be a therapeutic for a common form of non-Hodgkin’s lymphoma

By Steve Berberich
April 16, 2010

A team of scientists has discovered that a small compound, identified by computational chemists at the University of Maryland School of Pharmacy, can kill cancer cells of an aggressive form of non-Hodgkin’s lymphoma.

The research findings were published April 13 in the journal Cancer Cell. Professors Alexander MacKerell Jr., PhD, and Andrew Coop, PhD, MA, researchers at the School’s Computer-Aided Drug Design (CADD) Center, discovered a small molecule that decouples proteins that contribute to a form of cancer known as diffuse large B-cell lymphoma (DLBCL). This type of cancer accounts for as much as 30 percent of newly reported cases of lymphoma.

“This discovery indicates that a small molecule has the potential to be a therapeutic for a very common form of non-Hodgkin’s lymphoma, which is presently very difficult to treat,” said Coop, professor and chair of the School’s Department of Pharmaceutical Sciences. “It has huge potential for cancer therapy.”

At the CADD Center, of which he is director, MacKerell and team members directed specially designed computer models to find among millions of chemicals those most likely to disrupt protein-to-protein interactions thought to contribute to DLBCL. From about 200 candidates selected from the screen, several – including one labeled simply 79-6 – were identified to inhibit DLBCL. In the laboratories of collaborators Ari Melnick, MD, associate professor, Weill Cornell Medical College, and Gil Privý, PhD, professor, University of Toronto, experiments revealed that 79-6 was nontoxic in animal experiments and could kill human lymphoma cells.

MacKerell said, “We were able to find a small molecule that inhibited the interaction of a transcriptional factor called B-cell lymphoma protein [BCL6] and its partner proteins, which was then shown by our collaborators to be a potential treatment for DLBCL.”

Transcriptional factor proteins read and interpret the genetic “blueprint” in the DNA, and scientists have associated the BCL6 transcriptional factor with development of large cell lymphomas.

Because the discovery delved into the intimacy of interactions between proteins involved in transcription, MacKerell added, “I think the discovery may lead to a new category of cancer treatments.”

The collaboration was typical of CADD efforts in drug discovery studies, the co-authors said. The Center was formally created in 2001 to foster collaborative research among biologists, biophysicists, structural biologists, and computational scientists. The goal is to initiate these collaborations, in turn leading to research projects to discover chemical entities with the potential to be developed into novel therapeutic agents.

According to the Lymphoma Research Foundation Web site, there are more than 60 non-Hodgkin’s lymphomas (NHLs). Of these, it says of DLBCL, “Large cell lymphomas are the most common type of lymphoma, comprising about 30 percent (to) 40 percent of NHLs. The median age of those affected is 57, with a range of 10 to 88 years. Although most frequently seen in adults, large cell lymphomas may also be seen in children. These aggressive cancers may arise in lymph nodes or in extranodal sites, including the gastrointestinal tract, testes, thyroid, skin, breast, central nervous system or bone.”