Pharmacological reactivation of mutant p53: from protein structure to the cancer patient

APR-246/PRIMA-1 MET rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with p63 mutations

“…Various strategies have been developed to target mutant p53 for cancer treatment. Small molecules that bind to mutant p53 and restore wild-type function have been identified (30). In the present study, we asked whether one such compound, APR-246, could reactivate endogenous mutant p63 with amino acid substitutions in the DNA-binding domain in keratinocytes derived from patients with the EEC syndrome.…”

Preferential killing of p53-deficient cancer cells by reversine

“…9,21 For instance, pharmacological compounds have been designed that can bind specific p53 mutants to restore a conformation (and functionality) similar to that of the WT protein. 22,23 Alternatively, as in many tumors p53 is inactive secondary to the overexpression of the ubiquitin ligase HDM2 (which normally controls p53 levels by targeting it to proteasomal degradation), compounds that specifically target the p53-HDM2 interaction have been developed. 24,25 These agents, including the so-called nutlins, function by stabilizing p53 and can induce cancer cell death in a relatively selective fashion, a property that justifies their extensive characterization in ongoing clinical trials (http:// clinicaltrials.gov).…”

Small Molecule Structure Correctors Abolish Detrimental Effects of Apolipoprotein E4 in Cultured Neurons

“…Mutations in p53 result in an instability in the protein, preventing normal target interaction and usually causing accumulation to high concentrations in tumor cells. The mutant p53 prevents apoptosis and sustains tumor cell growth by impairing the ability of the p53 to bind to DNA and regulate gene transcription (75)(76)(77). Small molecules that restore p53 activity and conformation have been identified (77)(78)(79)(80)(81)(82).…”