Researchers from the Sackler Center at Weill Cornell Medical College have designed a new class of drugs that targets BCL6, a master regulatory protein responsible for causing the most common type of non-Hodgkin's lymphoma.
Findings published in today's issue of Cancer Cell show that an experimental compound designed by a team of researchers from Weill Cornell Medical College, the University of Maryland and the Ontario Cancer Center at the University of Toronto may effectively block the cancer-causing actions of BCL6 by attaching to a critical "hot spot" on its surface, thus killing off the cancer cells.
"BCL6 mediates its cancer-causing actions by attaching to other proteins," explains Dr. Ari Melnick, associate professor of medicine from the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College. "Traditionally protein-protein interactions have been viewed as being too difficult to block with small-molecule drugs."
Accordingly, by observing the atomic scale structure of BCL6 attached to its partner proteins, Dr. Melnick and colleagues identified a critical "hot spot" that appeared to be amenable to designing a drug. Dr. Alexander Mackerell, from the University of Maryland, then used computational modeling to identify chemical structures that could attack this hot spot.
"We tested the ability of a large number of these chemicals to bind and block BCL6," said Dr. Melnick, "and then Dr. Gilbert Priv-, from the University of Toronto, performed nuclear magnetic resonance and X-ray crystallography studies to show that a specific BCL6 inhibitor compound hit exactly in the center of the predicted hot spot. Our results show that given the right scientific approach it is quite possible to design drugs against key protein regulatory factors like BCL6."
Dr. Melnick's group showed that the BCL6 inhibitor was specific for BCL6 and did not block other master regulators, and that the experimental drug could powerfully kill DLBCL cells derived from human patients with this disease. Remarkably, the compound was completely non-toxic to animals, and could powerfully suppress and improve survival in animal models.
"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," explains Dr. Melnick. "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."
Dr. Melnick is among the physician-scientists supported by the Leukemia and Lymphoma Society's (LLS) Scholar Award Program. Since 2005, LLS has funded research in Dr. Melnick's laboratory, much of which has been focused on developing better treatments for patients with B-cell lymphomas. Dr. Melnick is also the leader of a Samuel Waxman Cancer Research Foundation Program Grant, which directly supported the effort to design small molecules for the BCL6 hot spot by the Melnick, Priv- and Mackerell research team. The results of Dr. Melnick's work in this area led the LLS to form a drug discovery partnership with Forma Therapeutics to improve these drugs so they can be used in human clinical trials for hematological malignant cancers.