Reactivating mutant p53 using small molecules as zinc metallochaperones: awakening a sleeping giant in cancer.

Abstract

Tumor protein p53 (TP53) is the most commonly mutated gene in human cancer. The majority of mutations are missense, and generate a defective protein that is druggable. Yet, for decades, the small-molecule restoration of wild-type (WT) p53 function in mutant p53 tumors (so-called p53 mutant 'reactivation') has been elusive to researchers. The p53 protein requires the binding of a single zinc ion for proper folding, and impairing zinc binding is a major mechanism for loss of function in missense mutant p53. Here, we describe recent work defining a new class of drugs termed zinc metallochaperones that restore WT p53 structure and function by restoring Zn(2+) to Zn(2+)-deficient mutant p53.

• Authors: Adam R Blanden, Xin Yu, Stewart N Loh, Arnold J Levine, Darren R Carpizo
• Journal: Drug discovery today (Drug Discov Today) Vol. 20 Issue 11 Pg. 1391-7 (11 2015) ISSN: 1878-5832 [Electronic] England
• PMID: 26205328 (Publication Type: Journal Article, Review, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• Metallochaperones
• Tumor Suppressor Protein p53
• Zinc

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Drug Design
• Humans
• Metallochaperones (metabolism)
• Mutation, Missense
• Neoplasms (drug therapy, genetics, pathology)
• Protein Folding (drug effects)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Zinc (metabolism)