Biological and Medicinal Chemistry

Rationally Designed Potent BMX Inhibitors Reveals Mode of Covalent Binding at the Atomic Level


BMX is pursued as a drug target because of its role in various pathophysiological processes. We designed BMX covalent inhibitors with single-digit nanomolar potency with unexploited topological pharmacophore patterns. Importantly, we reveal the first X-ray crystal structure of covalently inhibited BMX at Cys496, which displays key interactions with Lys445, responsible for hampering ATP catalysis and the DFG-out-like motif, typical of an inactive conformation. Molecular dynamic simulations also showed this interaction for two ligand/BMX complexes. Kinome selectivity profiling showed that the most potent compound JS25 is the strongest binder and displays intracellular target engagement in BMX-transfected cells with two-digit nanomolar inhibitory potency. The new inhibitors displayed anti-proliferative effects in androgen-receptor positive prostate cancer cells that where further increased when combined with known inhibitors of related signaling pathways, such as PI3K, AKT and Androgen Receptor. We expect these findings to guide development of new selective BMX therapeutic approaches.


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Supplementary material

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Graphical Abstract
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Supporting Information