Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53

Abstract

The mutational landscape of p53 in cancer is unusual among tumor suppressors because most of the alterations are of the missense type and localize to a single domain: the ~220 amino acid DNA-binding domain. Nearly all of these mutations produce the common effect of reducing p53’s ability to interact with DNA and activate transcription. Despite this seemingly simple phenotype, no mutant p53-targeted drugs are available to treat cancer patients. One of the main reasons for this is that the mutations exert their effects via multiple mechanisms—loss of DNA contacts, reduction in zinc-binding affinity, and lowering of thermodynamic stability—each of which involves a distinct type of physical impairment. This review discusses how this knowledge is informing current efforts to develop small molecules that repair these defects and restore function to mutant p53. Categorizing the spectrum of p53 mutations into discrete classes based on their inactivation mechanisms is the initial step toward personalized cancer therapy based on p53 allele status.

p53, A Victim of the Prion Fashion

“…The ReACp53 peptide targets the aggregation ability of mutant p53 and restores a partial function of the mutant protein, thereby inducing tumor shrinking both in vitro and in vivo [ 166 , 167 ]. These strategies, among others [ 168 ], seem to lead to mutant p53 refolding, allowing for a functional recovery of the protein.…”

Recent Synthetic Approaches towards Small Molecule Reactivators of p53

“…Answering whether heterogeneous oligomers are on-or off-pathway intermediates and investigating those involved in cancer through different methods, such as cryo-EM and super resolution microscopy, will definitely point oncogenic mutants of p53 as potential targets for anticancer therapy [11].Another promising strategy for the restoration of wild-type p53 function in tumors that have lost p53 tumor suppressor activity is the identification of natural or synthetic small organic molecules that can reactivate mutant p53 to its wild-type version. As a result, a large number of research groups have been focusing in the last few years on the synthesis of small molecules with p53-related activity and important advances have been accomplished thus far [12][13][14][15][16][17][18].As mentioned before, TP53 is mutated in around 50% of human cancers. Other cases include different reasons for p53 activity impairment, such as the oncogene MDM2 overexpression, which leads to WTp53 inactivation.…”

“…With this aim in mind, several strategies were designed in order to recapitulate p53 function in cancer. Overall, they include the use of small molecule or peptide stabilizers of misfolded p53, zinc administration, gene therapy, metallochaperones, alkylating and DNA intercalators, [34] blockage of p53-MDM2 interaction, impaired reactive oxygen species (ROS) detoxification and other p53 regulators [17,18,33,35].In this sense, this review will focus on the recent currently adopted methods for the activation and reactivation of the p53 tumor suppressor function with an emphasis on the synthetic approaches to obtain the small molecules used as reactivators. Although most of the mechanisms involved in such processes are still not completely known, this review will approach the reactivation of p53 via two main pathways: (1) The reactivation of mutant p53 via the covalent reaction with thiol in the cysteine residues and other approaches and (2) reactivation of wild-type p53 via the antagonists of the p53-MDM2/MDMX interactions.…”

“…Another promising strategy for the restoration of wild-type p53 function in tumors that have lost p53 tumor suppressor activity is the identification of natural or synthetic small organic molecules that can reactivate mutant p53 to its wild-type version. As a result, a large number of research groups have been focusing in the last few years on the synthesis of small molecules with p53-related activity and important advances have been accomplished thus far [12][13][14][15][16][17][18].…”

“…With this aim in mind, several strategies were designed in order to recapitulate p53 function in cancer. Overall, they include the use of small molecule or peptide stabilizers of misfolded p53, zinc administration, gene therapy, metallochaperones, alkylating and DNA intercalators, [34] blockage of p53-MDM2 interaction, impaired reactive oxygen species (ROS) detoxification and other p53 regulators [17,18,33,35].…”