Figure 3. Strategies targeting p53 and mutant p53.

(A) Reactivation of mutant p53. Direct binding of a small molecule (gray boxes) to a mutant p53 promotes and stabilizes WT p53 folding and conformation, leading to restoration of specific DNA binding and transcription of p53 target genes. This will induce tumor cell apoptosis or senescence. (B) Inhibition of MDM2. MDM2 binds to p53 directly through its N-termini and inhibits p53 function through two major mechanisms: (a) upon binding, MDM2 ubiquitinates p53, promoting proteasomal degradation of p53; (b) MDM2 promotes export of p53 out of the cell nucleus. (C) Depletion of mutant p53. Small molecules inhibit MTp53 gain-of-function and dominant-negative effects through degradation of MTp53.