Cargando…

Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics

Restoration of wild-type structure and function to mutant p53 with a small molecule (hereafter referred to as “reactivating” mutant p53) is one of the holy grails in cancer therapeutics. The majority of TP53 mutations are missense which generate a defective protein that is targetable. We are current...

Descripción completa

Detalles Bibliográficos
Autores principales: Kogan, Samuel, Carpizo, Darren R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025018/
https://www.ncbi.nlm.nih.gov/pubmed/29843463
http://dx.doi.org/10.3390/cancers10060166
_version_ 1783336187227799552
author Kogan, Samuel
Carpizo, Darren R.
author_facet Kogan, Samuel
Carpizo, Darren R.
author_sort Kogan, Samuel
collection PubMed
description Restoration of wild-type structure and function to mutant p53 with a small molecule (hereafter referred to as “reactivating” mutant p53) is one of the holy grails in cancer therapeutics. The majority of TP53 mutations are missense which generate a defective protein that is targetable. We are currently developing a new class of mutant p53 reactivators called zinc metallochaperones (ZMCs) and, here, we review our current understanding of them. The p53 protein requires the binding of a single zinc ion, coordinated by four amino acids in the DNA binding domain, for proper structure and function. Loss of the wild-type structure by impairing zinc binding is a common mechanism of inactivating p53. ZMCs reactivate mutant p53 using a novel two-part mechanism that involves restoring the wild-type structure by reestablishing zinc binding and activating p53 through post-translational modifications induced by cellular reactive oxygen species (ROS). The former causes a wild-type conformation change, the later induces a p53-mediated apoptotic program to kill the cancer cell. ZMCs are small molecule metal ion chelators that bind zinc and other divalent metal ions strong enough to remove zinc from serum albumin, but weak enough to donate it to mutant p53. Recently we have extended our understanding of the mechanism of ZMCs to the role of cells’ response to this zinc surge. We found that cellular zinc homeostatic mechanisms, which normally function to maintain free intracellular zinc levels in the picomolar range, are induced by ZMCs. By normalizing zinc levels, they function as an OFF switch to ZMCs because zinc levels are no longer sufficiently high to maintain a wild-type structure. This on/off switch leads to a transient nature to the mechanism of ZMCs in which mutant p53 activity comes on in a few hours and then is turned off. This finding has important implications for the translation of ZMCs to the clinic because it indicates that ZMC concentrations need not be maintained at high levels for their activity. Indeed, we found that short exposures (as little as 15 min) were adequate to observe the mutant p53 reactivating activity. This switch mechanism imparts an advantage over other targeted therapeutics in that efficacy can be accomplished with minimal exposure which minimizes toxicity and maximizes the therapeutic window. This on/off switch mechanism is unique in targeted cancer therapeutics and will impact the design of human clinical trials.
format Online
Article
Text
id pubmed-6025018
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-60250182018-07-09 Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics Kogan, Samuel Carpizo, Darren R. Cancers (Basel) Review Restoration of wild-type structure and function to mutant p53 with a small molecule (hereafter referred to as “reactivating” mutant p53) is one of the holy grails in cancer therapeutics. The majority of TP53 mutations are missense which generate a defective protein that is targetable. We are currently developing a new class of mutant p53 reactivators called zinc metallochaperones (ZMCs) and, here, we review our current understanding of them. The p53 protein requires the binding of a single zinc ion, coordinated by four amino acids in the DNA binding domain, for proper structure and function. Loss of the wild-type structure by impairing zinc binding is a common mechanism of inactivating p53. ZMCs reactivate mutant p53 using a novel two-part mechanism that involves restoring the wild-type structure by reestablishing zinc binding and activating p53 through post-translational modifications induced by cellular reactive oxygen species (ROS). The former causes a wild-type conformation change, the later induces a p53-mediated apoptotic program to kill the cancer cell. ZMCs are small molecule metal ion chelators that bind zinc and other divalent metal ions strong enough to remove zinc from serum albumin, but weak enough to donate it to mutant p53. Recently we have extended our understanding of the mechanism of ZMCs to the role of cells’ response to this zinc surge. We found that cellular zinc homeostatic mechanisms, which normally function to maintain free intracellular zinc levels in the picomolar range, are induced by ZMCs. By normalizing zinc levels, they function as an OFF switch to ZMCs because zinc levels are no longer sufficiently high to maintain a wild-type structure. This on/off switch leads to a transient nature to the mechanism of ZMCs in which mutant p53 activity comes on in a few hours and then is turned off. This finding has important implications for the translation of ZMCs to the clinic because it indicates that ZMC concentrations need not be maintained at high levels for their activity. Indeed, we found that short exposures (as little as 15 min) were adequate to observe the mutant p53 reactivating activity. This switch mechanism imparts an advantage over other targeted therapeutics in that efficacy can be accomplished with minimal exposure which minimizes toxicity and maximizes the therapeutic window. This on/off switch mechanism is unique in targeted cancer therapeutics and will impact the design of human clinical trials. MDPI 2018-05-29 /pmc/articles/PMC6025018/ /pubmed/29843463 http://dx.doi.org/10.3390/cancers10060166 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Kogan, Samuel
Carpizo, Darren R.
Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics
title Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics
title_full Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics
title_fullStr Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics
title_full_unstemmed Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics
title_short Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics
title_sort zinc metallochaperones as mutant p53 reactivators: a new paradigm in cancer therapeutics
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025018/
https://www.ncbi.nlm.nih.gov/pubmed/29843463
http://dx.doi.org/10.3390/cancers10060166
work_keys_str_mv AT kogansamuel zincmetallochaperonesasmutantp53reactivatorsanewparadigmincancertherapeutics
AT carpizodarrenr zincmetallochaperonesasmutantp53reactivatorsanewparadigmincancertherapeutics