Journal Article

Drugging the p53 pathway: understanding the route to clinical efficacy

Lane, David P., Khoo, Kian Hoe, Verma, Chandra S.

2014

Overview

Key Points Several drugs that target the tumour suppressor p53 pathway are now in clinical trials. Small-molecule drugs that inhibit the protein–protein interaction between p53 and the E3 ubiquitin protein ligase MDM2 have been developed by many academic and pharmaceutical groups; some can induce complete regressions in xenograft models of human cancer. Stapled peptides are an alternative to classical small-molecule inhibitors; they are active in animal models of cancer as dual inhibitors of the p53–MDM2 and p53–MDM4 interactions. The potential side effects of activating p53 in normal tissues are still being explored. So far, the major effect seems to be the induction of neutropenia. The activation of p53 by the MDM2 inhibitors can induce growth arrest, senescence or apoptosis in tumour cells. Studies to understand this variation have identified expression levels of key components of both the intrinsic and extrinsic apoptotic machinery as key regulators. Drug combinations that target these apoptotic pathways may increase the efficacy of p53 therapy. Drugs that reactivate the wild-type functions of mutant p53 are also in clinical trials, although their mechanism of action is still unclear. Structural studies of mutant p53 are providing druggable sites on the surface of the protein to which small molecules can bind. As well as inducing apoptotic death in cancer cells, the p53 pathway has a role in preventing the earliest development of cancer. This surveillance function of p53 is distinct and involves a discrete group of p53-induced genes that regulate DNA repair and metabolism, and does not require the genes encoding p53-upregulated modulator of apoptosis ( PUMA ), phorbol-12-myristate-13-acetate-induced protein 1 ( PMAIP1 ; also known as NOXA ) or cyclin-dependent kinase inhibitor 1A ( CDKN1A ). The p53-inducing drugs may have a role in chemoprevention. The tumour suppressor p53 is the most frequently mutated gene in human cancer, and drugs that restore or activate the p53 pathway have now reached clinical trials. Most of these drugs inhibit MDM2, a negative regulator of p53. In this Review, Lane and colleagues provide an overview of the different therapeutic approaches to targeting the p53 pathway and discuss the state of development of p53 pathway modulators. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/308/153 / 692/308/2779/109 / 692/699/67 / Animals / Antineoplastic Agents - chemistry / Antineoplastic Agents - metabolism / Antineoplastic Agents - therapeutic use / Biomedicine / Biotechnology / Cancer / Cancer Research / Care and treatment / Clinical Trials as Topic - methods / Drug Discovery - methods / Drug Discovery - trends / Humans / Medicinal Chemistry / Molecular Medicine / Neoplasms - drug therapy / Neoplasms - metabolism / Pharmacology, Experimental / Pharmacology/Toxicology / Protein Binding - physiology / Protein Structure, Tertiary / Protein-protein interactions / review-article / Signal Transduction - drug effects / Signal Transduction - physiology / Testing / Treatment Outcome / Tumor suppressor genes / Tumor Suppressor Protein p53 - antagonists & inhibitors / Tumor Suppressor Protein p53 - chemistry / Tumor Suppressor Protein p53 - metabolism