Low Molecular Weight Drug Blocks Action of Lymphoma Oncogene

Depletion or blockade of BCL6 potently kills lymphoma cells in tissue culture, and BCL6 is thus a critical therapeutic target. Like many oncogenes and tumor suppressors, BCL6 is a transcription factor.

Investigators at the Weill Cornell Medical College (New York, NY, USA) used an integrated biochemical and computational approach to identify small molecules that could specifically disrupt the activity of BCL6 by blocking its interaction with its corepressors BCOR, N-CoR, and SMRT.

They reported in the April 13, 2010, issue of the journal Cancer Cell that they had identified a low-molecular-weight drug that bound to the corepressor binding groove of the BCL6 BTB domain. This compound disrupted BCL6/corepressor complexes in vitro and in vivo, and it was observed by X-ray crystallography and NMR to bind to the critical site within the BTB groove. This compound could induce expression of BCL6 target genes and kill BCL6-positive lymphoma cell lines. In xenotransplantation experiments, the compound was nontoxic and potently suppressed lymphoma tumors in vivo. The compound also killed primary lymphomas from human patients.

"BCL6 mediates its cancer-causing actions by attaching to other proteins,” explained senior author Dr. Ari Melnick, associate professor of medicine at Weill Cornell Medical College. "Traditionally protein-protein interactions have been viewed as being too difficult to block with small-molecule drugs.”

"Our results show that given the right scientific approach it is quite possible to design drugs against key protein regulatory factors like BCL6,” said Dr. Melnick. "The BCL6 inhibitor was specific for BCL6 and did not block other master regulators. This means that if given as a therapeutic agent, the compound would be unlikely to have ill effects on healthy normal cells, and therefore would not be expected to have significant side effects. Since emerging data implicates BCL6 in other tumor types in addition to non-Hodgkin's lymphoma, it is possible that BCL6-targeted therapy could benefit many other cancer patients.”

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Weill Cornell Medical College