Abstract
mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives.
mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signalling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents.
This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD- 8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data.
Keywords: ATP-competitive, cancer, inhibitors, mTOR, rapamycin, serine-threonine kinase, mammalian target of rapamycin, mTORC1, mTORC2, PI3K
Current Medicinal Chemistry
Title: ATP-Competitive Inhibitors of mTOR: An Update
Volume: 18 Issue: 20
Author(s): S. Schenone, C. Brullo, F. Musumeci, M. Radi and M. Botta
Affiliation:
Keywords: ATP-competitive, cancer, inhibitors, mTOR, rapamycin, serine-threonine kinase, mammalian target of rapamycin, mTORC1, mTORC2, PI3K
Abstract: mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives.
mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signalling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents.
This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD- 8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data.
Export Options
About this article
Cite this article as:
Schenone S., Brullo C., Musumeci F., Radi M. and Botta M., ATP-Competitive Inhibitors of mTOR: An Update, Current Medicinal Chemistry 2011; 18 (20) . https://dx.doi.org/10.2174/092986711796391651
DOI https://dx.doi.org/10.2174/092986711796391651 |
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
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
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Recent Progress in Studying Curcumin and its Nano-preparations for Cancer Therapy
Current Pharmaceutical Design Inhibitors of Steroidal Cytochrome P450 Enzymes as Targets for Drug Development
Recent Patents on Anti-Cancer Drug Discovery The Role of Iron Chelation in Cancer Therapy
Current Medicinal Chemistry Smart Stimuli Sensitive Nanogels in Cancer Drug Delivery and Imaging: A Review
Current Pharmaceutical Design Branched Peptides as Therapeutics
Current Protein & Peptide Science Distinctive Phenotype Identification for Breast Cancer Genotypes Among Hereditary Breast Cancer Mutated Genes
Current Bioinformatics Thymoquinone Glucuronide Conjugated Magnetic Nanoparticle for Bimodal Imaging and Treatment of Cancer as a Novel Theranostic Platform
Current Radiopharmaceuticals Sympathetic Signaling in Angiogenesis: Implications for Cancer Progression
Current Cancer Therapy Reviews A Review on Application of Particle Swarm Optimization in Bioinformatics
Current Bioinformatics Autotaxin and Lysophosphatidic Acid Receptors as Novel Targets for the Radiosensitization of Tumor Vasculature in Non-Small Cell Lung Cancer
Current Angiogenesis (Discontinued) Meet Our Regional Editor
MicroRNA Use of Recombinant Human Erythropoietin as an Antianemic and Performance Enhancing Drug
Current Pharmaceutical Biotechnology NO News is not Necessarily Good News in Cancer
Current Cancer Drug Targets Natural Resins and Bioactive Natural Products thereof as Potential Anitimicrobial Agents
Current Pharmaceutical Design Renaissance of the Biologically Active Vitamin A Derivatives: Established and Novel Directed Therapies for Cancer and Chemoprevention
Current Pharmaceutical Design Genomic Sequence Analysis of EGFR Regulation by MicroRNAs in Lung Cancer
Current Topics in Medicinal Chemistry Insights into the Structure, Function, and Regulation of Human Cytochrome P450 1A2
Current Drug Metabolism Perspectives of New Therapies for Endometriosis
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Anti-inflammatory Action of Green Tea
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Drug Design for Protein Kinases and Phosphatases: Flexible-Receptor Docking, Binding Affinity and Specificity, and Drug-Binding Kinetics
Current Pharmaceutical Design