Targeting mutant p53 for improved cancer therapy

Abstract

Pharmacological restoration of wild-type activity to mutant p53 has emerged as a promising strategy for improved cancer therapy. This should restore p53-dependent apoptosis in response to oncogenic stress and thus eliminate the tumor. Mutant p53 reactivation may also lead to inhibition of mutant p53 gain-of-function activities that promote tumor growth, and act synergistically with conventional chemotherapeutic agents and radiotherapy. Several small molecules that target mutant p53 and restore wild-type conformation, and/or preferentially target mutant p53-expressing tumor cells, have been identified. Strategies for identification of such compounds include both rational design, based on detailed structural studies of mutant p53, and random screening of chemical libraries using protein or cellular assays. The mutant p53-reactivating compounds PRIMA-1 and APR-246 (PRIMA-1MET) modify cysteines in the p53 core domain by Michael addition. Mutant versions of p53 family members p63 and p73 can be targeted as well. The safety of APR-246 has been tested in a phase I clinical trial. Further studies should address the molecular mechanism of mutant p53 reactivation in more detail and assess clinical antitumor efficacy.