Abstract
Phosphatidylinositol 3-kinases (PI3Ks) are a class of lipid kinases that phosphorylate phosphatidylinositol 4,5- bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mTOR, and therefore play important roles in cell growth, survival, etc. The phosphatase and tensin homolog deleted in chromosome ten (PTEN), acts as the catalytic antagonist of PI3K by dephosphorylating PIP3 to PIP2. PI3K has become an important drug target for cancer therapy, since gain-of-function mutations of PIK3CA encoding PI3Kα, as well as loss-of-function mutations of PTEN, have been frequently found in human cancers. The pharmaceutical development of PI3K inhibitors has made a great leap forward during the last 3 years. While PI3Kβ, & δ and γ isoform-specific PI3K inhibitors (TGX-221, IC87114 and AS-605240) have been developed for therapy of coronary heart disease, asthma, and glomerulonephritis, respectively, a promising PI3Kα specific inhibitor is not yet available. Correspondingly, almost all of the promising PI3K inhibitors under development for caner therapy, such as NVP-BEZ235, GDC-0941 and ZSTK474, are pan-PI3K isoform inhibitors. Each of these pan-PI3K inhibitors seems to induce a common G1 phase arrest. All have shown favorable in vivo anticancer efficacies and low toxicities, and therefore most have entered evaluation in clinical trials. P-Akt and p-S6 have been reported to be feasible pharmacodynamic biomarkers for monitoring the efficacy of these agents. In the process of discovery of these and other PI3K inhibitors, detailed structure-activity relationship studies were carried out. This review summarizes key advances in the development of PI3K inhibitors, which is preceded by an introduction of PI3K family and their functions.
Keywords: Phosphatidylinositol 3-kinase inhibitor, cancer, biomarker, structure-activity relationship
Current Medicinal Chemistry
Title: Advances in Development of Phosphatidylinositol 3-Kinase Inhibitors
Volume: 16 Issue: 22
Author(s): Dexin Kong and Takao Yamori
Affiliation:
Keywords: Phosphatidylinositol 3-kinase inhibitor, cancer, biomarker, structure-activity relationship
Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are a class of lipid kinases that phosphorylate phosphatidylinositol 4,5- bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mTOR, and therefore play important roles in cell growth, survival, etc. The phosphatase and tensin homolog deleted in chromosome ten (PTEN), acts as the catalytic antagonist of PI3K by dephosphorylating PIP3 to PIP2. PI3K has become an important drug target for cancer therapy, since gain-of-function mutations of PIK3CA encoding PI3Kα, as well as loss-of-function mutations of PTEN, have been frequently found in human cancers. The pharmaceutical development of PI3K inhibitors has made a great leap forward during the last 3 years. While PI3Kβ, & δ and γ isoform-specific PI3K inhibitors (TGX-221, IC87114 and AS-605240) have been developed for therapy of coronary heart disease, asthma, and glomerulonephritis, respectively, a promising PI3Kα specific inhibitor is not yet available. Correspondingly, almost all of the promising PI3K inhibitors under development for caner therapy, such as NVP-BEZ235, GDC-0941 and ZSTK474, are pan-PI3K isoform inhibitors. Each of these pan-PI3K inhibitors seems to induce a common G1 phase arrest. All have shown favorable in vivo anticancer efficacies and low toxicities, and therefore most have entered evaluation in clinical trials. P-Akt and p-S6 have been reported to be feasible pharmacodynamic biomarkers for monitoring the efficacy of these agents. In the process of discovery of these and other PI3K inhibitors, detailed structure-activity relationship studies were carried out. This review summarizes key advances in the development of PI3K inhibitors, which is preceded by an introduction of PI3K family and their functions.
Export Options
About this article
Cite this article as:
Kong Dexin and Yamori Takao, Advances in Development of Phosphatidylinositol 3-Kinase Inhibitors, Current Medicinal Chemistry 2009; 16 (22) . https://dx.doi.org/10.2174/092986709788803222
DOI https://dx.doi.org/10.2174/092986709788803222 |
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
-
Fitness or Fatness: The Debate Continues for AMP-Activated Protein Kinase in Heart Function
Current Cardiology Reviews Older Adults Prescribed Methadone: A Review of the Literature Across the Life Span from Opiate Initiation to Methadone Maintenance Treatment
Current Drug Abuse Reviews Relevance of Sphingolipids in the Pleiotropic Protective Effects of High-Density Lipoproteins
Current Pharmaceutical Design A Link Between Hypertension and Atrial Fibrillation: Methods of Treatment and Prevention
Current Vascular Pharmacology Natural Products as a Source of Antiarrhythmic Drugs
Mini-Reviews in Medicinal Chemistry A Review of Hypertension Management in Atrial Fibrillation
Current Hypertension Reviews Potential Anti-cancer Drugs Commonly Used for Other Indications
Current Cancer Drug Targets Current Place of Beta-Blockers in the Treatment of Hypertension
Current Vascular Pharmacology Atrial Natriuretic Peptide: Structure, Function, and Physiological Effects: A Narrative Review
Current Cardiology Reviews Exploring the Potential of NO-Independent Stimulators and Activators of Soluble Guanylate Cyclase for the Medical Treatment of Erectile Dysfunction
Current Pharmaceutical Design Editorial [Hot Topic: Waiting for Action on the Osteoarthritis Front (Guest Editors: Virginia Byers Kraus and Thomas Aigner)]
Current Drug Targets Implantable Medical Devices and Tissue Engineering: An Overview of Manufacturing Processes and the Use of Polymeric Matrices for Manufacturing and Coating their Surfaces
Current Medicinal Chemistry Targeting Cancer Stem Cell Lines as a New Treatment of Human Cancer
Recent Patents on Anti-Cancer Drug Discovery Hypoxia-Inducible Factor-1 in Arterial Disease: A Putative Therapeutic Target
Current Vascular Pharmacology Kinins as Therapeutic Agents in Cardiovascular and Renal Diseases
Current Pharmaceutical Design Meet Our Editorial Board Member
Current Stem Cell Research & Therapy Inhibitory Effects of Some Bryophytes on Glutathione-S -Transferase
Current Enzyme Inhibition Endothelial Dysfunction and Coronary Atherosclerosis
Current Drug Targets - Cardiovascular & Hematological Disorders Antimicrobial Action of Chelating Agents: Repercussions on the Microorganism Development, Virulence and Pathogenesis
Current Medicinal Chemistry Challenges and Promises of Developing Thrombin Receptor Antagonists
Recent Patents on Cardiovascular Drug Discovery