Researchers from the Sackler Center at Weill Cornell Medical College (WCMC) have designed a new class of drugs that targets a master regulatory protein responsible for causing the most common type of non-Hodgkin's lymphoma.
Findings published April 14 in Cancer Cell (17:4) show that an experimental compound designed by the researchers and colleagues may effectively block the cancer-causing actions of the protein known as BCL6 by attaching to a critical "hot spot" on its surface, thus killing the cancer cells.
"BCL6 mediates its cancer-causing actions by attaching to other proteins," says co-author Dr. Ari Melnick, associate professor of medicine at WCMC. "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, Melnick and colleagues identified a hot spot that appeared to be amenable to designing a drug. Co-author Alexander Mackerell of the University of Maryland then used computational modeling to identify chemical structures that could attack this spot.
"We tested the ability of a large number of these chemicals to bind and block BCL6," said Melnick, and then using nuclear magnetic resonance and X-ray crystallography studies, colleagues showed "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."
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 the cancer cells cells derived from human patients with non-Hodgkin's lymphoma. Remarkably, the compound was completely nontoxic 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," Melnick said. "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."
The research was supported by the Leukemia and Lymphoma Society (LLS) and the Samuel Waxman Cancer Research Foundation. The results of Melnick's work has 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.