DESIGN, SYNTHESIS AND CHARACTERISATION OF A NOVEL TYPE II B-RAF PARADOX BREAKER INHIBITOR
Résumé
The mutation V600E in B-Raf leads to MAPK pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors, such as vemurafenib (1) and PLX4720 (4) efficiently block the MAPK pathways in B-Raf mutant cells, however these inhibitors induce conformational changes in the wild type B-Raf (wt B-Raf) kinase domain leading to heterodimerisation with C-Raf, causing paradoxical hyperactivation of the MAPK pathway. This unwanted activation may be avoided by another class of inhibitors (type II) which bind the kinase in the DFG-out conformation, such as AZ628 (3) preventing heterodimerization. Here we present a new B-Raf kinase domain inhibitor that represents a hybrid between 4 and 3. This novel inhibitor borrows the hinge binding region from 4 and the back pocket binding moiety from 3. We designed, synthesized, determined its binding mode, performed activity/selectivity studies, and molecular dynamics simulations in order to study the conformational effects induced by this inhibitor on wt and V600E mutant B-Raf kinase. We discovered that the inhibitor binds in a DFG-out/αC-helix-in conformation, did not induce the aforementioned paradoxical hyperactivation in the MAPK pathway, and it was active and highly selective for B-Raf. We propose that this merging approach can be used to design a novel class of B-Raf inhibitors for translational studies.
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