Abstract
The MDM2 oncogene is overexpressed in various human cancers. Its expression correlates with the phenotypes of high-grade, late-stage, and more resistant tumors. The auto-regulatory loop between MDM2 and the tumor suppressor p53 has long been considered the epitome of a rational target for cancer therapy. As such, many novel agents have been generated to interfere with the interaction of the two proteins, which results in the activation of p53. Among these agents are several small molecule inhibitors synthesized based upon the crystal structures of the MDM2-p53 complex. With use of high-throughput screening, several specific and effective agents for inhibition of the protein-protein interaction were discovered. Recent investigations, however, have demonstrated that many proteins regulate the MDM2-p53 interaction, and that MDM2 may have p53-independent oncogenic functions. In order for novel MDM2 inhibitors to be translated to the clinic, it is necessary to obtain a better understanding of the regulation of MDM2 and of the MDM2-p53 interaction. In particular, the implications of various interactions between certain regulator(s) and MDM2/p53 under different circumstances need to be elucidated to determine which pathway(s) represent the best targets for therapy. Targeting both MDM2 itself and regulators of MDM2 and the MDM2-p53 interaction, or use of MDM2 inhibitors in combination with conventional treatments, may improve prospects for tumor eradication.
Keywords: MDM2, p53, oncogene, regulation, protein-protein interaction, apoptosis, cell cycle arrest
Anti-Cancer Agents in Medicinal Chemistry
Title: Recent Advances in Validating MDM2 as a Cancer Target
Volume: 9 Issue: 8
Author(s): Elizabeth R. Rayburn, Scharri J. Ezell and Ruiwen Zhang
Affiliation:
Keywords: MDM2, p53, oncogene, regulation, protein-protein interaction, apoptosis, cell cycle arrest
Abstract: The MDM2 oncogene is overexpressed in various human cancers. Its expression correlates with the phenotypes of high-grade, late-stage, and more resistant tumors. The auto-regulatory loop between MDM2 and the tumor suppressor p53 has long been considered the epitome of a rational target for cancer therapy. As such, many novel agents have been generated to interfere with the interaction of the two proteins, which results in the activation of p53. Among these agents are several small molecule inhibitors synthesized based upon the crystal structures of the MDM2-p53 complex. With use of high-throughput screening, several specific and effective agents for inhibition of the protein-protein interaction were discovered. Recent investigations, however, have demonstrated that many proteins regulate the MDM2-p53 interaction, and that MDM2 may have p53-independent oncogenic functions. In order for novel MDM2 inhibitors to be translated to the clinic, it is necessary to obtain a better understanding of the regulation of MDM2 and of the MDM2-p53 interaction. In particular, the implications of various interactions between certain regulator(s) and MDM2/p53 under different circumstances need to be elucidated to determine which pathway(s) represent the best targets for therapy. Targeting both MDM2 itself and regulators of MDM2 and the MDM2-p53 interaction, or use of MDM2 inhibitors in combination with conventional treatments, may improve prospects for tumor eradication.
Export Options
About this article
Cite this article as:
Rayburn R. Elizabeth, Ezell J. Scharri and Zhang Ruiwen, Recent Advances in Validating MDM2 as a Cancer Target, Anti-Cancer Agents in Medicinal Chemistry 2009; 9 (8) . https://dx.doi.org/10.2174/187152009789124628
DOI https://dx.doi.org/10.2174/187152009789124628 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...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
Related Articles
-
Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair
CNS & Neurological Disorders - Drug Targets Calcitonin-Derived Carrier Peptides
Current Pharmaceutical Design Therapeutic Peptide Mimetics Looking for a Turn to Block Aberrant Players of Malignancy
Current Cancer Therapy Reviews Insights into Immunophilin Structure and Function
Current Medicinal Chemistry The Therapeutical Potential of a Novel Pterocarpanquinone LQB-118 to Target Inhibitor of Apoptosis Proteins in Acute Myeloid Leukemia Cells
Anti-Cancer Agents in Medicinal Chemistry Application of NMR to the Study of Cells and Body Fluids
Current Organic Chemistry Glycoconjugates in Cancer Therapy
Anti-Cancer Agents in Medicinal Chemistry Bioinformatics Approach to BDNF and BDNF-Related Disorders
Current Neuropharmacology Heparin Oligosaccharides as Potential Therapeutic Agents in Senile Dementia
Current Pharmaceutical Design Phosphorylation-Dephosphorylation Imbalance of Cytoskeletal Associated Proteins in Neurodegenerative Diseases
Recent Patents on CNS Drug Discovery (Discontinued) Phospholipase A2 Isoforms as Novel Targets for Prevention and Treatment of Inflammatory and Oncologic Diseases
Current Drug Targets Positive Social Interactions in a Lifespan Perspective with a Focus on Opioidergic and Oxytocinergic Systems: Implications for Neuroprotection
Current Neuropharmacology Bacterial Toxins: Potential Weapons Against HIV Infection
Current Pharmaceutical Design Non-Genotoxic p53-Activators and their Significance as Antitumor Therapy of Future
Current Medicinal Chemistry Receptor Dimerization - Rationale for the Design of Bivalent Ligands
Current Topics in Medicinal Chemistry CD248: Reviewing its Role in Health and Disease
Current Drug Targets A Peptide Based Pro-Drug Ameliorates Amyloid-β Induced Neuronal Apoptosis in In Vitro SH-SY5Y Cells
Current Alzheimer Research Thyroid Hormone Modulation of Immunity: Its Participation in Chronic Stress-Induced Immune Alterations
Current Immunology Reviews (Discontinued) Decreasing the Metastatic Potential in Cancers - Targeting the Heparan Sulfate Proteoglycans
Current Drug Targets Opioid Growth Factor and its Derivatives as Potential Non-toxic Multifunctional Anticancer and Analgesic Compounds
Current Medicinal Chemistry