Drugging the p53 Pathway: Understanding the Route to Clinical Efficacy

Nat Rev Drug Discov. 2014 Mar;13(3):217-36. doi: 10.1038/nrd4236.

Abstract

The tumour suppressor p53 is the most frequently mutated gene in human cancer, with more than half of all human tumours carrying mutations in this particular gene. Intense efforts to develop drugs that could activate or restore the p53 pathway have now reached clinical trials. The first clinical results with inhibitors of MDM2, a negative regulator of p53, have shown efficacy but hint at on-target toxicities. Here, we describe the current state of the development of p53 pathway modulators and new pathway targets that have emerged. The challenge of targeting protein-protein interactions and a fragile mutant transcription factor has stimulated many exciting new approaches to drug discovery.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use
  • Clinical Trials as Topic / methods
  • Drug Discovery / methods*
  • Drug Discovery / trends
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Protein Binding / physiology
  • Protein Structure, Tertiary
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Treatment Outcome
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / chemistry*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antineoplastic Agents
  • Tumor Suppressor Protein p53