An integrated view of p53 dynamics, function, and reactivation

The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials. Novel approaches for targeting TP53 nonsense mutations are also underway. This Review discusses recent progress in pharmacological reactivation of mutant p53 and highlights problems and promises with these strategies.

Inactivation of the transcription factor p53, through either direct mutation or aberrations in one of its many regulatory pathways, is a hallmark of virtually every tumor. In recent years, screening for p53 activators and a better understanding of the molecular mechanisms of oncogenic perturbations of p53 function have opened up a host of novel avenues for therapeutic intervention in cancer: from the structure-guided design of chemical chaperones to restore the function of conformationally unstable p53 cancer mutants, to the development of potent antagonists of the negative regulators MDM2 and MDMX and other modulators of the p53 pathway for the treatment of cancers with wild-type p53. Some of these compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, personalized anticancer medicines. We trace the structural evolution of the p53 pathway, from germ-line surveillance in simple multicellular organisms to its pluripotential role in humans.

The majority of currently used therapeutics are small molecule-based and utilize occupancy-driven pharmacology as the mode of action (MOA), in which the protein function is modulated via temporary inhibition. New modalities that operate using alternative MOAs are essential for tapping into the “undruggable” proteome. The PROteolysis Targeting Chimera (PROTAC) technology provides an attractive new approach that utilizes an event-driven MOA. Small molecule-based heterobifunctional PROTACs modulate protein target levels by hijacking the ubiquitin-proteasome system to induce degradation of the target. Here, we address important milestones in the development of the PROTAC technology, as well as emphasize key findings from this previous year and highlight future directions of this promising drug discovery modality.