Small‐molecule stabilization of the p53 – 14‐3‐3 protein‐protein interaction

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 effica...

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Vydané v:	FEBS letters Ročník 591; číslo 16; s. 2449 - 2457
Hlavní autori:	Doveston, Richard G., Kuusk, Ave, Andrei, Sebastian A., Leysen, Seppe, Cao, Qing, Castaldi, Maria P., Hendricks, Adam, Brunsveld, Luc, Chen, Hongming, Boyd, Helen, Ottmann, Christian
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England 01.08.2017
Predmet:	14-3-3 Proteins - chemistry 14-3-3 Proteins - metabolism 14‐3‐3 proteins fluorescence polarization Glycosides - pharmacology humans isothermal titration calorimetry Models, Molecular mutation neoplasms p53 PPI stabilization Protein Binding - drug effects protein crystallography Protein Stability Protein Structure, Secondary protein-protein interactions therapeutics Tumor Suppressor Protein p53 - chemistry Tumor Suppressor Protein p53 - metabolism 14-3-3 proteins PPI stabilization protein crystallography fluorescence polarization isothermal titration calorimetry p53
ISSN:	0014-5793, 1873-3468, 1873-3468
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Correspondence-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0014-5793 1873-3468 1873-3468
DOI:	10.1002/1873-3468.12723