Journal
FEBS LETTERS
Volume 591, Issue 16, Pages 2449-2457Publisher
WILEY
DOI: 10.1002/1873-3468.12723
Keywords
14-3-3 proteins; fluorescence polarization; isothermal titration calorimetry; p53; PPI stabilization; protein crystallography
Funding
- European Union through AEGIS [67555, 705188]
- Marie Curie Actions (MSCA) [705188] Funding Source: Marie Curie Actions (MSCA)
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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.
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