Small molecule modulation of protein-protein interactions is a very promising but also challenging area in drug discovery. The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. Protein-protein interactions can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by pharmaceutical industry and academia, the opposite strategy of stabilizing protein-protein interactions still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific protein-protein interactions. In this review, we give an overview of 14-3-3 interactions with p53, explain isoform specific stabilization of the tumor suppressor protein, explore the approach of stabilizing the 14-3-3σ - p53 complex and summarize some promising small-molecules inhibiting the p53 - MDM2 protein-protein interaction.
- 14-3-3 - p53 protein-protein interaction stabilization
- MDM2-p53 protein-protein interaction inhibition