![conference banner](/images/conference-banner.jpeg)
Abstract
The tumor suppressor protein p53 is inactivated in all types of human cancers, either by negative regulation, by mutation or deletion of its gene. Specifically, in tumors that retain wild-type (wt) p53 status, p53 is inactivated by interaction with negative regulators, such as MDM2 and MDMX. These two proteins are found to be overexpressed in several different types of cancers, and the restoration of p53 activity by inhibition of these proteins is now considered an important approach for cancer treatment. The first studies using this strategy to reactivate wt p53 were focused on the development of small molecules that could inhibit MDM2. In this way, p53 could be liberated and act again as a tumor suppressor. From these studies, nine small molecules have reached clinical trials. More recently, MDMX was also identified as an important therapeutic target to efficiently reactivate wt p53, and it is now considered that, for full p53 reactivation, dual inhibition of MDM2 and MDMX is required. In this review we will focus on the most recent advances in the discovery of novel small molecules and stapled peptides that act as selective MDMX inhibitors or as dual MDM2/X inhibitors.
Keywords: Anti-tumor agents, dual inhibitors, MDMX, MDM2, protein-protein interaction inhibitors, p53, p53 reactivation, small molecules.
Graphical Abstract
Current Topics in Medicinal Chemistry
Title:An Update on MDMX and Dual MDM2/X Inhibitors
Volume: 18 Issue: 8
Author(s): Margarida Espadinha, Valentina Barcherini, Elizabeth A. Lopes and Maria M.M. Santos*
Affiliation:
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa. Av. Prof. Gama Pinto, 1649-003 Lisbon,Portugal
Keywords: Anti-tumor agents, dual inhibitors, MDMX, MDM2, protein-protein interaction inhibitors, p53, p53 reactivation, small molecules.
Abstract: The tumor suppressor protein p53 is inactivated in all types of human cancers, either by negative regulation, by mutation or deletion of its gene. Specifically, in tumors that retain wild-type (wt) p53 status, p53 is inactivated by interaction with negative regulators, such as MDM2 and MDMX. These two proteins are found to be overexpressed in several different types of cancers, and the restoration of p53 activity by inhibition of these proteins is now considered an important approach for cancer treatment. The first studies using this strategy to reactivate wt p53 were focused on the development of small molecules that could inhibit MDM2. In this way, p53 could be liberated and act again as a tumor suppressor. From these studies, nine small molecules have reached clinical trials. More recently, MDMX was also identified as an important therapeutic target to efficiently reactivate wt p53, and it is now considered that, for full p53 reactivation, dual inhibition of MDM2 and MDMX is required. In this review we will focus on the most recent advances in the discovery of novel small molecules and stapled peptides that act as selective MDMX inhibitors or as dual MDM2/X inhibitors.
Export Options
About this article
Cite this article as:
Espadinha Margarida , Barcherini Valentina , Lopes A. Elizabeth and Santos M.M. Maria*, An Update on MDMX and Dual MDM2/X Inhibitors, Current Topics in Medicinal Chemistry 2018; 18 (8) . https://dx.doi.org/10.2174/1568026618666180604080119
DOI https://dx.doi.org/10.2174/1568026618666180604080119 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Medicinal Chemistry Advancement in Life-Threatening Diseases
The current issue will highlight concise reports that specify ground-breaking insights, including the novel discovery of drug targets and their action mechanism or drugs of novel classes. These are projected to encourage medicinal chemistry future efforts to address the most challenging medical needs. The current issue highlights further efforts to ...read more
![](/images/wayfinder.jpg)
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Role of YY1 in Oncogenesis and Its Potential as a Drug Target in Cancer Therapies
Current Cancer Drug Targets Target Driven Preclinical Screening for New Antimitotic Chemotherapy Agents
Current Topics in Medicinal Chemistry A Common Biological Mechanism in Cancer and Alzheimers Disease?
Current Alzheimer Research Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of the VHL Mutation p.P81S (c.241C>T)
Current Genomics MicroRNAs: Modulators of Cell Identity, and their Applications in Tissue Engineering
MicroRNA The Pathogenesis of Susceptibility to Acute Kidney Injury in the Elderly
Current Aging Science Natural Product Inhibitors of Hsp90: Potential Leads for Drug Discovery
Mini-Reviews in Medicinal Chemistry Sirolimus Eluting Stent: A New Era in Interventional Cardiology?
Current Pharmaceutical Design Multiple Forms of Proteasomes and their Role in Tumor Fate
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery (Discontinued) Epigenetics in Cystic Fibrosis: Epigenetic Targeting of a Genetic Disease
Current Drug Targets Immunotherapy with Tumor Vaccines for the Treatment of Malignant Gliomas
Current Drug Discovery Technologies Mammalian Target of Rapamycin (mTOR) Inhibitors as Anti-Cancer Agents
Current Cancer Drug Targets Exploiting Novel Cell Cycle Targets in the Development of Anticancer Agents
Current Cancer Drug Targets Molecular Studies on Novel Antitumor Bis 1,4-Dihydropyridine Derivatives Against Lung Carcinoma and their Limited Side Effects on Normal Melanocytes
Anti-Cancer Agents in Medicinal Chemistry MicroRNAs in Cancer Gene Therapy: Another Look
Current Cancer Therapy Reviews The Genetic Basis of Human Cytomegalovirus Resistance and Current Trends in Antiviral Resistance Analysis
Infectious Disorders - Drug Targets Expression and Functions of Heat Shock Proteins in the Normal and Pathological Mammalian Eye
Current Molecular Medicine CD26/Dipeptidyl Peptidase IV as a Novel Therapeutic Target for Cancer and Immune Disorders
Mini-Reviews in Medicinal Chemistry Subtype Selectivity in Phosphodiesterase 4 (PDE4): A Bottleneck in Rational Drug Design
Current Pharmaceutical Design Anticancer Properties of Flavonoids: Roles in Various Stages of Carcinogenesis
Cardiovascular & Hematological Agents in Medicinal Chemistry