Protein kinases control various cellular processes such as cell division, proliferation, and differentiation. Small-molecule kinase inhibitors are useful tools for dissecting the functions of protein kinases in cells as they can acutely turn off the catalytic activity of kinases. Because dysregulation of the kinase activity in the cell signaling pathways can drive cancer growth, many protein kinases are pursued as therapeutic targets. While small-molecule kinase inhibitors have been developed as therapeutics for the treatment of cancer, the majority of them suffer from poor target selectivity because of the high homology in the catalytic domain among the hundreds of human kinases. Here we report a new strategy of rigidifying the inhibitors to achieve selective kinase inhibition. Specifically, we applied the ring closure strategy to a pyrazolo[3,4-d]pyrimidine-based inhibitor which afforded dramatic improvement in selectivity for RAF kinases. The optimized rigidified inhibitor potently blocked the activity of BRAFV600Eand the proliferation of cancer cells. More importantly, the optimized molecule selectively suppressed the cell proliferation in cancer cells harboring BRAFV600Ein a panel of 60 cancer cell lines. The crystal structures of optimized inhibitors bound to BRAF were solved to confirm the binding mode and further explain the improved selectivity.

Investigation of effects of rigidity on kinase inhibitor selectivity

2019 Spring National Meeting

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