2. Academic Validation
  3. Small-molecule stabilization of the p53 - 14-3-3 protein-protein interaction

Small-molecule stabilization of the p53 - 14-3-3 protein-protein interaction

  • FEBS Lett. 2017 Aug;591(16):2449-2457. doi: 10.1002/1873-3468.12723.
Richard G Doveston 1,  Ave Kuusk 1 2,  Sebastian A Andrei 1,  Seppe Leysen 1,  Qing Cao 3,  Maria P Castaldi 3,  Adam Hendricks 3,  Luc Brunsveld 1,  Hongming Chen 2,  Helen Boyd 2,  Christian Ottmann 1 4
Affiliations

Affiliations

  • 1 Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, The Netherlands.
  • 2 Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
  • 3 Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Waltham, MA, USA.
  • 4 Department of Chemistry, University of Duisburg-Essen, Germany.
PMID: 28640363 DOI: 10.1002/1873-3468.12723
Abstract

14-3-3 proteins are positive regulators of the tumor suppressor p53, the mutation of which is implicated in many human cancers. Current strategies for targeting of p53 involve restoration of wild-type function or inhibition of the interaction with MDM2, its key negative regulator. Despite the efficacy of these strategies, the alternate approach of stabilizing the interaction of p53 with positive regulators and, thus, enhancing tumor suppressor activity, has not been explored. Here, we report the first example of small-molecule stabilization of the 14-3-3 - p53 protein-protein interaction (PPI) and demonstrate the potential of this approach as a therapeutic modality. We also observed a disconnect between biophysical and crystallographic data in the presence of a stabilizing molecule, which is unusual in 14-3-3 PPIs.

Keywords

14-3-3 proteins; PPI stabilization; fluorescence polarization; isothermal titration calorimetry; p53; protein crystallography.

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