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

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Holvey RS, Valkov E, Neal D, Stewart M, Abell C
OpenAccess logo ChemMedChem 10 1232-9 (2015)
Related entries: 4u54, 4u58, 4u5l, 4u5n, 4u5o, 4u5s, 4u5v

Cited: 8 times
EuropePMC logo PMID: 25899172

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.

Articles - 4u5u mentioned but not cited (2)

  1. Selective Targeting of the TPX2 Site of Importin-α Using Fragment-Based Ligand Design. Holvey RS, Valkov E, Neal D, Stewart M, Abell C. ChemMedChem 10 1232-1239 (2015)
  2. PepPro: A Nonredundant Structure Data Set for Benchmarking Peptide-Protein Computational Docking. Xu X, Zou X. J Comput Chem 41 362-369 (2020)


Articles citing this publication (6)

  1. Structure of importin-α bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein. Nakada R, Hirano H, Matsuura Y. Sci Rep 5 15055 (2015)
  2. Computationally-guided optimization of small-molecule inhibitors of the Aurora A kinase-TPX2 protein-protein interaction. Cole DJ, Janecek M, Stokes JE, Rossmann M, Faver JC, McKenzie GJ, Venkitaraman AR, Hyvönen M, Spring DR, Huggins DJ, Jorgensen WL. Chem Commun (Camb) 53 9372-9375 (2017)
  3. Comparative study of the interactions between fungal transcription factor nuclear localization sequences with mammalian and fungal importin-alpha. Bernardes NE, Fukuda CA, da Silva TD, de Oliveira HC, de Barros AC, Dreyer TR, Bertolini MC, Fontes MRM. Sci Rep 10 1458 (2020)
  4. Development of a new benchmark for assessing the scoring functions applicable to protein-protein interactions. Han L, Yang Q, Liu Z, Li Y, Wang R. Future Med Chem 10 1555-1574 (2018)
  5. Mechanistic insights into the inhibitory activity of FDA approved ivermectin against SARS-CoV-2: old drug with new implications. Qureshi U, Mir S, Naz S, Nur-E-Alam M, Ahmed S, Ul-Haq Z. J Biomol Struct Dyn 40 8100-8111 (2022)
  6. Structural and calorimetric studies demonstrate that the hepatocyte nuclear factor 1β (HNF1β) transcription factor is imported into the nucleus via a monopartite NLS sequence. Wiedmann MM, Aibara S, Spring DR, Stewart M, Brenton JD. J Struct Biol 195 273-281 (2016)


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