Pharmacological targeting of mutant p53

Abstract

TP53 is the most commonly mutated gene in cancer, with over half of all human cancers harboring a mutation in the gene. The p53 protein is a transcription factor that functions as a tumor suppressor, and a subset of its numerous roles include the arrest of proliferation, promotion of DNA repair, and induction of apoptosis in cells with severe DNA damage or stress. The vast majority of p53 mutations are single amino acid substitutions within the DNA binding domain, which either directly impede the protein's ability to bind DNA or destabilize the structure, resulting in misfolding. These missense mutant proteins are found at high levels due to loss of the MDM2 mediated regulation, and consequently serve as potential drug targets. Numerous pharmacological approaches have been investigated to restore wild type p53 function to these mutants (so-called reactivating mutant p53) with some entering in clinical trials while most have failed in early development. Recently, the field of cancer drug development has produced a number of new compounds that continue to advance this field, each with a different mechanism of action. Here we sought to review these compounds and approaches to reactivating mutant p53. Given the large number of patients with missense mutant p53 mutations, reactivating mutant p53 remains a highly sought after goal in developmental therapeutics.