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.
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
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- 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
-
CDC25A and B Dual-Specificity Phosphatase Inhibitors: Potential Agents for Cancer Therapy
Current Medicinal Chemistry Polymeric Nanoparticles for Ophthalmic Drug Delivery: An Update on Research and Patenting Activity
Recent Patents on Nanomedicine Past, Present, and Future of Targeting Ras for Cancer Therapies
Mini-Reviews in Medicinal Chemistry Recent Progress and Related Patents on the Applications of Bone Marrow-Derived Stem/Progenitor Cells in Regenerative Medicine and Cancer Therapies
Recent Patents on Regenerative Medicine Platelets in Alzheimer’s Disease-Associated Cellular Senescence and Inflammation
Current Pharmaceutical Design MiR-492 as an Important Biomarker for Early Diagnosis and Targeted Treatment in Different Cancers
Current Cancer Therapy Reviews Protein Serine/Threonine Phosphotase-1 is Essential in Governing Normal Development of Vertebrate Eye
Current Molecular Medicine Advancing Drug Therapy for Brain Tumours: A Current Review of the Pro-inflammatory Peptide Substance P and its Antagonists as Anti-cancer Agents
Recent Patents on CNS Drug Discovery (Discontinued) Rb Function in the Apoptosis and Senescence of Non-Neuronal and Neuronal Cells: Role in Oncogenesis
Current Molecular Medicine Epigenetic Regulation and Therapeutic Approaches in Cancer
Current Topics in Medicinal Chemistry Podocyte Mitosis – A Catastrophe
Current Molecular Medicine New Thermoresponsive Eyedrop Formulation Containing Ibuprofen Loaded-Nanostructured Lipid Carriers (NLC): Development, Characterization and Biocompatibility Studies
Current Drug Delivery Scaffold Hopping for Identification of Novel PKCβII Inhibitors Based on Ligand and Structural Approaches, Virtual Screening and Molecular Dynamics Study
Combinatorial Chemistry & High Throughput Screening Geldanamycin, Radicicol, and Chimeric Inhibitors of the Hsp90 Nterminal ATP Binding Site
Current Topics in Medicinal Chemistry Signal Transduction Targets in Prostate Cancer
Current Signal Transduction Therapy Epstein-Barr Virus-associated Gastric Cancer and Potential Mechanisms of Oncogenesis
Current Cancer Drug Targets Anti-Apoptotic Genes in the Survival of Monocytic Cells During Infection
Current Genomics The Interest of Folic Acid in Targeted Photodynamic Therapy
Current Medicinal Chemistry Gene Delivery for Cancer Therapy
Current Drug Delivery Intercellular Genomic (Chromosomal) Variations Resulting in Somatic Mosaicism: Mechanisms and Consequences
Current Genomics