PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73

The low molecular weight compound PRIMA-1 and the structural analog PRIMA-1(MET), also named APR-246, reactivate mutant p53 through covalent binding to the core domain and induce apoptosis in tumor cells. Here, we asked whether PRIMA-1(MET)/APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. We found that PRIMA-1(MET)/APR-246 can restore the pro-apoptotic function to mutant TAp63 gamma and TAp73 beta in tumor cells but has less effect on TAp73 alpha. Moreover, PRIMA-1(MET)/APR-246-stimulated DNA binding of mutant TAp63 gamma and induced expression of the p53/p63/p73 downstream targets p21 and Noxa. The reactivation of mutant p53, p63 and p73 by PRIMA-1(MET)/APR-246 indicates a common mechanism, presumably involving homologous structural elements in the p53 family proteins. Our findings may open avenues for therapeutic intervention in human developmental disorders with mutations in p63. Oncogene (2010) 29, 6442-6451; doi:10.1038/onc.2010.382; published online 6 September 2010