Small‐molecule stabilization of the p53 – 14‐3‐3 protein‐protein interaction. Issue 16 (6th August 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: FEBS letters. Volume 591:Issue 16(2017)
• Page Start: 2449
• Page End: 2457
• Publication Date: 2017-08-06
• Subjects: 14‐3‐3 proteins -- fluorescence polarization -- isothermal titration calorimetry -- p53 -- PPI stabilization -- protein crystallography; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1002/1873-3468.12723
• Languages: English
• ISSNs: 0014-5793

Abstract

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. Abstract :