Document Detail


Targeting the ubiquitin-mediated proteasome degradation of p53 for cancer therapy.
MedLine Citation:
PMID:  23151129     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Within the past decade, there has been a revolution in the types of drugs developed to treat cancer. Therapies that selectively target cancer-specific aberrations, such as kinase inhibitors, have made a dramatic impact on a subset of patients. In spite of these successes, there is still a dearth of treatment options for the vast majority of patients. Therefore, there is a need to design therapies with broader efficacy. The p53 tumor suppressor pathway is one of the most frequently altered in human cancers. However, about half of all cancers retain wild-type p53, yet through various mechanisms, the p53 pathway is otherwise inactivated. Targeting this pathway for reactivation truly represents the "holy grail" in cancer treatment. Most commonly, destabilization of p53 by various components of ubiquitin- proteasome system, notably the ubiquitin ligase MDM2 and its partner MDMX as well as various deubiquitinating enzymes (DUBs), render p53 inert and unresponsive to stress signals. Reinstating its function in cancer has been a long sought-after goal. Towards this end, a great deal of work has been devoted to the development of compounds that either interfere with the p53-MDM2 and p53- MDMX interactions, inhibit MDM2 E3 activity, or target individual DUBs. Here we review the current progress that has been made in the field, with a special emphasis on both MDM2 and DUB inhibitors. Developing inhibitors targeting the upstream of the p53 ubiquitination pathway will likely also be a valuable option.
Authors:
Tiffany Devine; Mu-Shui Dai
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Review    
Journal Detail:
Title:  Current pharmaceutical design     Volume:  19     ISSN:  1873-4286     ISO Abbreviation:  Curr. Pharm. Des.     Publication Date:  2013  
Date Detail:
Created Date:  2013-04-25     Completed Date:  2013-10-28     Revised Date:  2014-05-01    
Medline Journal Info:
Nlm Unique ID:  9602487     Medline TA:  Curr Pharm Des     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  3248-62     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Drug Design
Enzyme Inhibitors / pharmacology
Humans
Neoplasms / drug therapy*,  pathology
Proteasome Endopeptidase Complex / metabolism
Proteasome Inhibitors / pharmacology
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
Tumor Suppressor Protein p53 / metabolism*
Ubiquitin / metabolism
Ubiquitination
Grant Support
ID/Acronym/Agency:
R00 CA127134/CA/NCI NIH HHS; R00 CA127134/CA/NCI NIH HHS; R01 CA160474/CA/NCI NIH HHS; R01 CA160474/CA/NCI NIH HHS; T32 GM071338/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Enzyme Inhibitors; 0/Proteasome Inhibitors; 0/Tumor Suppressor Protein p53; 0/Ubiquitin; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 6.3.2.19/MDM2 protein, human; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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