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
-
Differential Developmental Origin of Arteries: Impact on Angiogenesis and Arteriogenesis
Medicinal Chemistry Reviews - Online (Discontinued) SDH Genes: From Glomic Tumours to Pheochromocytomas
Current Hypertension Reviews Measurement of Physical Changes in the Myocardium for Development of Novel Methods for Diagnosing Ischemia
Current Cardiology Reviews The Effects of Italian Mediterranean Organic Diet (IMOD) on Health Status
Current Pharmaceutical Design New Insight into Urate-Related Mechanism of Cardiovascular Damage
Current Pharmaceutical Design Role of Nut Consumption in the Management of Cognitive Decline - A Mini-Review
Current Alzheimer Research Advanced Glycation and ROS: A Link between Diabetes and Heart Failure
Current Vascular Pharmacology Let Them Eat Cake
Current Nutrition & Food Science Indian Spices for Healthy Heart - An Overview
Current Cardiology Reviews PDE5 Inhibitor Treatment Options for Urologic and Non-Urologic Indications: 2012 Update
Current Pharmaceutical Design Relevance of Endothelial-Haemostatic Dysfunction in Cigarette Smoking
Current Medicinal Chemistry The J-shaped Association Between Alcohol Consumption and Breast Cancer: A Case-Control Study
Current Nutrition & Food Science Genomics and the Prospects of Existing and Emerging Therapeutics for Cardiovascular Diseases
Current Pharmaceutical Design The Importance of Reendothelialization After Arterial Injury
Current Pharmaceutical Design Hypertension in Obstructive Sleep Apnoea
Vascular Disease Prevention (Discontinued) The Tree of Sirtuins and the Garden of Cardiovascular Youth
Current Vascular Pharmacology The Critical Role of Toll-Like Receptor Signaling Pathways in the Induction and Progression of Autoimmune Diseases
Current Molecular Medicine Genetic Signatures in the Treatment of Stroke
Current Pharmaceutical Design COVID-19: Are Experimental Drugs a Cure or Cause?
Current Drug Safety <i>Prunella vulgaris</i> L: Critical Pharmacological, Expository Traditional Uses and Extensive Phytochemistry: A Review
Current Drug Discovery Technologies