Abstract
Phosphoinositide 3-kinases (PI3Ks) control key signaling pathways in cancer cells, leading to cell proliferation, survival, motility and angiogenesis. In several human cancers, activation of PI3Ks results from gain-of-function or over-expression of PI3Ks and/or hyperactivity of up- or downstream players in the pathway. As inhibition of PI3Ks and downstream targets such as mammalian target of rapamycin (mTOR) has been shown to reduce tumor growth in vitro and in preclinical models, several small molecule inhibitors of PI3Ks are currently undergoing clinical trial as novel agents in cancer therapy. These drugs include inhibitors targeting all class I PI3Ks (α, β, γ, δ isoforms), compounds blocking selective PI3K isoforms and dual inhibitors active on both PI3Ks and mTOR. Herein, we summarize the pharmacology and preliminary clinical data of the main PI3K inhibitors undergoing clinical trial. We will also review the preclinical studies documenting the major effects of systemic PI3K inhibition on non-cancer tissues, which have shed light on potential side effects, caveats and limitations for PI3K blockade in patients.
Keywords: PI3K, mTOR, Akt, cancer, enzyme inhibitors, Phosphoinositide, proliferation, survival, motility, angiogenesis
Current Medicinal Chemistry
Title: Present and Future of PI3K Pathway Inhibition in Cancer: Perspectives and Limitations
Volume: 18 Issue: 18
Author(s): E. Ciraolo, F. Morello and E. Hirsch
Affiliation:
Keywords: PI3K, mTOR, Akt, cancer, enzyme inhibitors, Phosphoinositide, proliferation, survival, motility, angiogenesis
Abstract: Phosphoinositide 3-kinases (PI3Ks) control key signaling pathways in cancer cells, leading to cell proliferation, survival, motility and angiogenesis. In several human cancers, activation of PI3Ks results from gain-of-function or over-expression of PI3Ks and/or hyperactivity of up- or downstream players in the pathway. As inhibition of PI3Ks and downstream targets such as mammalian target of rapamycin (mTOR) has been shown to reduce tumor growth in vitro and in preclinical models, several small molecule inhibitors of PI3Ks are currently undergoing clinical trial as novel agents in cancer therapy. These drugs include inhibitors targeting all class I PI3Ks (α, β, γ, δ isoforms), compounds blocking selective PI3K isoforms and dual inhibitors active on both PI3Ks and mTOR. Herein, we summarize the pharmacology and preliminary clinical data of the main PI3K inhibitors undergoing clinical trial. We will also review the preclinical studies documenting the major effects of systemic PI3K inhibition on non-cancer tissues, which have shed light on potential side effects, caveats and limitations for PI3K blockade in patients.
Export Options
About this article
Cite this article as:
Ciraolo E., Morello F. and Hirsch E., Present and Future of PI3K Pathway Inhibition in Cancer: Perspectives and Limitations, Current Medicinal Chemistry 2011; 18 (18) . https://dx.doi.org/10.2174/092986711796011193
DOI https://dx.doi.org/10.2174/092986711796011193 |
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
-
Synthesis and Biological Evaluation of Some Novel Thiazolylhydrazinomethylideneferrocenes as Antimicrobial Agents
Letters in Drug Design & Discovery Editorial (Thematic Issue: Targeted Therapies)
Mini-Reviews in Medicinal Chemistry Patent Selections
Recent Patents on Computer Science Integrins as Novel Drug Targets for Overcoming Innate Drug Resistance
Current Cancer Drug Targets Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) and Microsatellite Instability in Patients with Colorectal Cancer and Its Clinical Features
Current Molecular Medicine Nanoparticle Coated Viral Vectors for Gene Therapy
Current Biotechnology Mixed Micelles as Nano Polymer Therapeutics of Docetaxel: Increased In vitro Cytotoxicity and Decreased In vivo Toxicity
Current Drug Delivery Magnetic Resonance Imaging of Uncommon Hepatic Mesenchymal Tumours: Haemangioendothelioma and Angiosarcoma
Current Medical Imaging Synthesis, Characterization and Cholinesterase Inhibition Studies of New Arylidene Aminothiazolylethanone Derivatives
Medicinal Chemistry Apoptosis in Obstructive Nephropathy
Current Pediatric Reviews Pharmacological Inhibition of Poly(ADP-ribose) Polymerase (PARP) Activity in PARP-1 Silenced Tumour Cells Increases Chemosensitivity to Temozolomide and to a N3-Adenine Selective Methylating Agent
Current Cancer Drug Targets Leptin: The Prototypic Adipocytokine and its Role in NAFLD
Current Pharmaceutical Design Aurora Kinases and Passenger Proteins as Targets for Cancer Therapy: An Update
Current Enzyme Inhibition Editorial (Thematic Issue: Immune Modulation)
Current Pharmaceutical Design Long Noncoding RNA MALAT1: Insights into its Biogenesis and Implications in Human Disease
Current Pharmaceutical Design Mechanisms for Targeted Delivery of Nanoparticles in Cancer
Current Pharmaceutical Design A New “Era” for the α7-nAChR
Current Drug Targets Cratylia mollis Lectin: A Versatile Tool for Biomedical Studies
Current Bioactive Compounds Garlic and its Organosulfides as Potential Chemopreventive Agents: A Review
Current Cancer Therapy Reviews A Novel Highly Selective Cannabinoid CB2 Agonist Reduces in vitro Growth and TGF-beta Release of Human Glial Cell Tumors
Central Nervous System Agents in Medicinal Chemistry