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Protein-protein interactions are difficult therapeutic targets, and inhibiting pathologically relevant interactions without disrupting other essential ones presents an additional challenge. Herein we report how this might be achieved for the potential anticancer target, the TPX2-importin-α interaction. Importin-α is a nuclear transport protein that regulates the spindle assembly protein TPX2. It has two binding sites--major and minor-to which partners bind. Most nuclear transport cargoes use the major site, whereas TPX2 binds principally to the minor site. Fragment-based approaches were used to identify small molecules that bind importin-α, and crystallographic studies identified a lead series that was observed to bind specifically to the minor site, representing the first ligands specific for this site. Structure-guided synthesis informed the elaboration of these fragments to explore the source of ligand selectivity between the minor and major sites. These ligands are starting points for the development of inhibitors of this protein-protein interaction.

Original publication




Journal article



Publication Date





1232 - 1239


cancer, fragment-based ligand design, nuclear transporters, protein-protein interactions, structure-guided ligand design, Binding Sites, Cell Cycle Proteins, Humans, Ligands, Microtubule-Associated Proteins, Models, Molecular, Molecular Structure, Nuclear Proteins, Protein Binding, Small Molecule Libraries, alpha Karyopherins