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Selective Targeting of the TPX2 Site of Importin alpha Using Fragment-Based Ligand Design

DOI: 10.1002/cmdc.201500014 DOI Help
PMID: 25899172 PMID Help

Authors: Rhian S. Holvey (University of Cambridge) , Eugene Valkov (MRC Laboratory of Molecular Biology, Cambridge, U.K.) , David Neal (University of Cambridge) , Murray Stewart (MRC Laboratory of Molecular Biology) , Chris Abell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: ChemMedChem

State: Published (Approved)
Published: April 2015
Diamond Proposal Number(s): 8547

Open Access Open Access

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-a interaction. Importina 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-a, 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.

Journal Keywords: Cancer; Fragment-Based Ligand Design; Nuclear Transporters; Protein–Protein Interactions; Structure-Guided Ligand Design

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Other Facilities: ESRF

Added On: 14/06/2015 18:08

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