Postdoctoral fellow in Molecular Biology
Université de Montréal
Award-winning publication: Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization
Published in: Nature Chemical Biology, 9(7), 428-436.
"The RAF protein often mutates into human cancer (some 7% of tumours). Still, and despite encouraging clinical results, the drugs that target the protein are often ineffective against the disease. In certain cases, the drugs tend to stimulate the enzymatic activity of RAF rather than slow it down. The paradox has troubled an entire community of clinicians and researchers. Our study, conducted in close collaboration with the Lunenfeld-Tanenbaum Research Institute, sheds light on the molecular mechanism that creates these "paradoxical" effects. In fact, we determined that the inhibitors block the RAF protein in a closed conformation that closely resembles an active form. This conformation triggers dimerization—the transformation of a monomer into a structure made up of two molecules—with another RAF protein that is not linked to the inhibitor, which is then forced to take on an active conformation."
Pharmaceutical companies have invested astronomical sums to develop drugs that target the RAF protein. Hugo Lavoie's discovery of the mechanism by which the RAF protein dimerizes when coupled with medication will significantly impact the research field. The model that he contributed designing partly explains the adverse effects of existing drugs and could lead to the development of new strategies to inhibit this key enzyme. Drug design efforts focused on the dimerization process may open new doors in the treatment of RAF-dependent cancers.