BCL6 is the most commonly involved oncogene in diffuse large B cell lymphomas (DLBCL). Previous work has shown that BCL6 is required for survival of lymphoma cells and that blockade of the gene potently kills DLBCL cells. However, although BCL6 it a very attractive therapeutic target, it has not been considered to be particularly amenable to targeting with small molecules.

"Like many oncogenes, BCL6 is a transcription factor," says senior study author Dr. Ari Melnick from Weill Cornell Medical College in New York. "Transcription factors like BCL6 usually exert their actions through extensive interactions with other proteins. In general, small molecule inhibitors with the potential to become drug candidates have been considered not likely to effectively disrupt protein-protein interactions."

Dr. Melnick and colleagues used structure-based strategies to determine where the best point of attack would be to disrupt the activity of BCL6. Using computer-aided drug design combined with functional assays, the researchers identified small molecule compounds that specifically interacted with BCL6 at an exposed groove within the BCL6 BTB domain. The researchers were interested in this specific part of BCL6 because it is the binding site of cofactors required for BCL6 to carry out its cancer-causing functions.

One of the compounds that they identified, called 79-6, bound specifically to the BTB groove and effectively killed BCL6-positive DLBCL cell lines. Further, 79-6 markedly reduced BCL6-dependent tumors in mice that had received transplants of human lymphoma cells and specifically killed primary human DLBCL cells.

"Our work demonstrates that oncogenic transcriptional repressors can be therapeutically targeted with small molecules and presents a rationally designed therapy approach for treatment of lymphomas," concludes Dr. Melnick. "Future efforts will be taken to systematically improve the therapeutic potential of these compounds with the goal of developing BCL6 targeted therapy for DLBCL."

The researchers include Leandro C. Cerchietti, Weill Cornell Medical College, Cornell University, New York, NY; Alexandru F. Ghetu, Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Toronto, Canada; Xiao Zhu, University of Maryland, Baltimore, MD; Gustavo F. Da Silva, University of Maryland, Baltimore, MD; Shijun Zhong, University of Maryland, Baltimore, MD; Marilyn Matthews, University of Maryland, Baltimore, MD; Karen L. Bunting, Weill Cornell Medical College, Cornell University, New York, NY; Jose M. Polo, Albert Einstein College of Medicine, Bronx, NY; Christophe Fares, Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Toronto, Canada; Cheryl H. Arrowsmith, Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Toronto, Canada, University of Toronto, Toronto, Canada; Shao Ning Yang, Weill Cornell Medical College, Cornell University, New York, NY; Monica Garcia, Weill Cornell Medical College, Cornell University, New York, NY; Andrew Coop, University of Maryland, Baltimore, MD; Alexander D. MacKerell, Jr., University of Maryland, Baltimore, MD; Gilbert G. Prive, Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Toronto, Canada, University of Toronto, Toronto, Canada; and Ari Melnick, Weill Cornell Medical College, Cornell University, New York, NY.

Note: If no author is given, the source is cited instead.

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