Abstract
Since the discovery of p53 as “guardian of the genome” , a large number of efforts have been put in place in order to find molecular strategies aiming to restore p53 wild-type functions, particularly in the light of the fact that its pathway results ineffective in most tumors even though they have non-mutated p53. In this context, pediatric cancers, that are mostly p53 wild-type at the time of diagnosis, represent an ideal target for such therapeutic approach. Within the several mechanisms and proteins ruling p53 activity, the murine double minute 2 (MDM2) is its crucial negative regulator, frequently found overexpressed in p53-wild-type tumors. The development of new technologies such as nuclear magnetic resonance structure analyses, computational structure-based design studies, and library peptides screening have recently led to the discovery and characterization of a large number of compounds belonging to different chemical families that are able to target the interaction p53-MDM2, rescuing the p53 wild-type pathway with an overall pro-apoptotic and anticancer activity. Within the preclinical assessment of these molecules, the cis-imidazoline analogue Nutlin-3 has definitely attracted great interest for its in vitro and in vivo antitumor activity in several pediatric cancer models, either as single agent on in combination with standard chemotherapy. In this light, the aim of this review is to summarize the main preclinical evidences of the potential of MDM2 inhibitors for the treatment of childhood cancers and the key suggestions coming from their assessment in the treatment of adult cancers as proof of concept for future pediatric clinical studies.
Keywords: Clinical perspectives, innovative therapeutic combinations, MDM2-inhibitors, non genotoxic inhibitors, nutlins family, p53, pediatric tumors, pediatric preclinical testing program.
Current Medicinal Chemistry
Title:MDM2 Non-Genotoxic Inhibitors as Innovative Therapeutic Approaches for the Treatment of Pediatric Malignancies
Volume: 20 Issue: 17
Author(s): V. Tisato, A. Norcio, R. Voltan, C. Celeghini, D. Zella and P. Secchiero
Affiliation:
Keywords: Clinical perspectives, innovative therapeutic combinations, MDM2-inhibitors, non genotoxic inhibitors, nutlins family, p53, pediatric tumors, pediatric preclinical testing program.
Abstract: Since the discovery of p53 as “guardian of the genome” , a large number of efforts have been put in place in order to find molecular strategies aiming to restore p53 wild-type functions, particularly in the light of the fact that its pathway results ineffective in most tumors even though they have non-mutated p53. In this context, pediatric cancers, that are mostly p53 wild-type at the time of diagnosis, represent an ideal target for such therapeutic approach. Within the several mechanisms and proteins ruling p53 activity, the murine double minute 2 (MDM2) is its crucial negative regulator, frequently found overexpressed in p53-wild-type tumors. The development of new technologies such as nuclear magnetic resonance structure analyses, computational structure-based design studies, and library peptides screening have recently led to the discovery and characterization of a large number of compounds belonging to different chemical families that are able to target the interaction p53-MDM2, rescuing the p53 wild-type pathway with an overall pro-apoptotic and anticancer activity. Within the preclinical assessment of these molecules, the cis-imidazoline analogue Nutlin-3 has definitely attracted great interest for its in vitro and in vivo antitumor activity in several pediatric cancer models, either as single agent on in combination with standard chemotherapy. In this light, the aim of this review is to summarize the main preclinical evidences of the potential of MDM2 inhibitors for the treatment of childhood cancers and the key suggestions coming from their assessment in the treatment of adult cancers as proof of concept for future pediatric clinical studies.
Export Options
About this article
Cite this article as:
Tisato V., Norcio A., Voltan R., Celeghini C., Zella D. and Secchiero P., MDM2 Non-Genotoxic Inhibitors as Innovative Therapeutic Approaches for the Treatment of Pediatric Malignancies, Current Medicinal Chemistry 2013; 20 (17) . https://dx.doi.org/10.2174/0929867311320170007
DOI https://dx.doi.org/10.2174/0929867311320170007 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...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
-
Animal Modeling of Cancer Pathology and Studying Tumor Response to Therapy
Current Drug Targets How to Prevent Postpartum Relapse to Smoking
Current Pediatric Reviews Germinal and Somatic Trisomy 21 Mosaicism: How Common is it, What are the Implications for Individual Carriers and How Does it Come About?
Current Genomics Patents on Enhancing the Potency and Longevity of Highly Valuable Protein Hormones
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Modulating Interleukins and their Receptors Interactions with Small Chemicals Using In Silico Approach for Asthma
Current Topics in Medicinal Chemistry Cancer Risk and Nullity of Glutathione-S-Transferase Mu and Theta 1 in Occupational Pesticide Workers
Current Pharmaceutical Biotechnology Functional Genomics- and Network-driven Systems Biology Approaches for Pharmacogenomics and Toxicogenomics
Current Drug Metabolism Neurological Disorders of Purine and Pyrimidine Metabolism
Current Topics in Medicinal Chemistry Stem Cells and Combinatorial Science
Combinatorial Chemistry & High Throughput Screening EGFR(s) in Aging and Carcinogenesis of the Gastrointestinal Tract
Current Protein & Peptide Science Sulforaphane Treatment of Young Men with Autism Spectrum Disorder
CNS & Neurological Disorders - Drug Targets Epigenetic Effects of Environmental Chemicals on Reproductive Biology
Current Drug Targets Recent Progress in FKBP Ligand Development
Current Molecular Pharmacology Editorial
Current Medical Imaging Cardiac and Muscular Involvement in Idiopathic Inflammatory Myopathies: Noninvasive Diagnostic Assessment and the Role of Cardiovascular and Skeletal Magnetic Resonance Imaging
Inflammation & Allergy - Drug Targets (Discontinued) Gastroenterological Complications of Anderson-Fabry Disease
Current Pharmaceutical Design Meet Our Editorial Board Member
Current Respiratory Medicine Reviews COVID-19 in Pediatrics: A Systematic Review of Current Knowledge and Practice
Infectious Disorders - Drug Targets Polo-Like Kinase 1 as a Potential Therapeutic Target for Osteosarcoma
Current Pharmaceutical Design Pharmacogenomics in Drug Induced Liver Injury
Current Drug Metabolism