title: Selective Targeting of the TPX2 Site of Importin-α Using Fragment-Based Ligand Design.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK).
authors.forename: Rhian S
authors.initials: RS
authors.lastname: Holvey
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH (UK).
authors.forename: Eugene
authors.initials: E
authors.lastname: Valkov
authors.affiliation: University of Cambridge, Department of Oncology, Box 279, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ (UK).
authors.forename: David
authors.initials: D
authors.lastname: Neal
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH (UK).
authors.forename: Murray
authors.initials: M
authors.lastname: Stewart
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW (UK). ca26@cam.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Abell
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D028901:alpha Karyopherins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D018797:Cell Cycle Proteins; D008024:Ligands; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; C122167:TPX2 protein, human; D028901:alpha Karyopherins
keywords: cancer; fragment-based ligand design; nuclear transporters; protein-protein interactions; structure-guided ligand design