Low Molecular Weight Drug Neutralizes Lymphoma Oncogene

Drug developers have identified a low molecular weight compound that blocks the activity of the protein encoded by the BCL6 oncogene and kills lymphoma cells both in culture and in an animal model.

A multinational team from three universities, Weill Cornell Medical College (New York, NY, USA), the University of Maryland (Baltimore, USA), and the University of Toronto (Canada) combined computer-aided drug design with functional assays to identify low-molecular-weight compounds that bound to the corepressor binding groove of the BCL6 BTB domain. Binding to this site neutralized the BCL6 protein, effectively preventing expression of the oncogene.

Detailed results published in the April 13, 2010, issue of the journal Cancer Cell revealed that the candidate drug could induce expression of genes usually silenced by BCL6 and kill BCL6-positive DLBCL cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed DLBCL tumors in vivo. The compound also killed primary DLBCLs from human patients.

"This is the first time a drug of this nature has been designed and it shows that it is not actually impossible to target factors like BCL6," said senior author Dr. Ari Melnick, associate professor of medicine at Weill Cornell Medical College. "It is a protein that controls the production of thousands of other genes, and because of that, it has a very profound impact on cells and is required for lymphoma cells to survive and multiply.”

"BCL6 causes the majority of diffuse large B cell lymphomas, the most common form of non-Hodgkin lymphoma, and currently, about 60% of diffuse large B cell lymphomas can be cured with chemo-immunotherapy,” said Dr. Melnick. "The hope is that we can improve that to a higher percent, and in the long term reduce the need for chemotherapy.”

Related Links:
Weill Cornell Medical College
University of Maryland
University of Toronto