Discovery of compounds that reactivate p53 mutants in vitro and in vivo

The tumor suppressor p53 is the most frequently mutated protein in human cancer. The majority of these mutations are missense mutations in the DNA binding domain of p53. Restoring p53 tumor suppressor function could have a major impact on the therapy for a wide range of cancers. Here we report a virtual screening approach that identified several small molecules with p53 reactivation activities. The UCI-LC0023 compound series was studied in detail and was shown to bind p53, induce a conformational change in mutant p53, restore the ability of p53 hotspot mutants to associate with chromatin, reestablish sequence-specific DNA binding of a p53 mutant in a reconstituted in vitro system, induce p53-dependent transcription programs, and prevent progression of tumors carrying mutant p53, but not p53(null) or p53(WT) alleles. Our study demonstrates feasibility of a computation-guided approach to identify small molecule corrector drugs for p53 hotspot mutations.

Automated summary

This study utilized a virtual screening approach to identify small molecules that can reactivate the tumor suppressor p53. The UCI-LC0023 compound series was explored in depth and shown to restore the function of mutant p53, prevent tumor progression in cells carrying mutant p53, and induce transcription programs dependent on p53 activity.