Abstract
Fibrosis of the lung and other organ systems is an increasing cause of morbidity and mortality worldwide. Effective anti-fibrotic agents for such disorders are currently lacking. Injury to epithelium-lined tissues in mammals is typically associated with a mesenchymal response, including the activation of myofibroblasts. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease that results from effacement of the normal alveolar architecture of the lung. Loss of lung capacity for gas-exchange and increased work of breathing eventually leads to respiratory failure and death. In cutaneous wound models, apoptosis of myofibroblasts are essential to scar-less wound healing. Recent studies indicate that acquisition of an apoptosis-resistant myofibroblast phenotype in the injured lung is associated with non-resolving and persistent fibrosis. The acquired resistance to apoptosis in myofibroblasts is mediated, at least in part, by the sustained activation of two critical pro-survival protein kinases, focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Therapeutic interventions that modulate the activity of these protein kinases with resultant alterations in the phenotype of myofibroblasts may prove to be effective anti-fibrotic therapeutic strategies. We discuss the potential roles for protein kinase inhibitors as novel drugs for fibrotic disorders. Progress in pre-clinical and clinical development of small molecule inhibitors targeting pro-survival protein kinases is reviewed.
Keywords: Fibrosis, protein kinase inhibitors, therapeutics, apoptosis, focal adhesion kinase, protein kinase B, fibroblasts, epithelial cells
Current Medicinal Chemistry
Title: Protein Kinase Inhibitors in the Treatment of Pulmonary Fibrosis
Volume: 15 Issue: 25
Author(s): Sylvie Garneau-Tsodikova and Victor J. Thannickal
Affiliation:
Keywords: Fibrosis, protein kinase inhibitors, therapeutics, apoptosis, focal adhesion kinase, protein kinase B, fibroblasts, epithelial cells
Abstract: Fibrosis of the lung and other organ systems is an increasing cause of morbidity and mortality worldwide. Effective anti-fibrotic agents for such disorders are currently lacking. Injury to epithelium-lined tissues in mammals is typically associated with a mesenchymal response, including the activation of myofibroblasts. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease that results from effacement of the normal alveolar architecture of the lung. Loss of lung capacity for gas-exchange and increased work of breathing eventually leads to respiratory failure and death. In cutaneous wound models, apoptosis of myofibroblasts are essential to scar-less wound healing. Recent studies indicate that acquisition of an apoptosis-resistant myofibroblast phenotype in the injured lung is associated with non-resolving and persistent fibrosis. The acquired resistance to apoptosis in myofibroblasts is mediated, at least in part, by the sustained activation of two critical pro-survival protein kinases, focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Therapeutic interventions that modulate the activity of these protein kinases with resultant alterations in the phenotype of myofibroblasts may prove to be effective anti-fibrotic therapeutic strategies. We discuss the potential roles for protein kinase inhibitors as novel drugs for fibrotic disorders. Progress in pre-clinical and clinical development of small molecule inhibitors targeting pro-survival protein kinases is reviewed.
Export Options
About this article
Cite this article as:
Garneau-Tsodikova Sylvie and Thannickal J. Victor, Protein Kinase Inhibitors in the Treatment of Pulmonary Fibrosis, Current Medicinal Chemistry 2008; 15 (25) . https://dx.doi.org/10.2174/092986708785908969
DOI https://dx.doi.org/10.2174/092986708785908969 |
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
-
Clinical Significance of miR-1826 as a Novel Prognostic Biomarker in Colorectal Cancer
Anti-Cancer Agents in Medicinal Chemistry Eph/Ephrin Signalling and Function in Oncogenesis: Lessons from Embryonic Development
Current Cancer Drug Targets Cancer-associated Autoantibodies as Biomarkers for Early Detection and Prognosis is Cancer: An Update
Current Cancer Therapy Reviews Reactive Oxygen Species in the Initiation of IL-4 Driven Autoimmunity as a Potential Therapeutic Target
Current Pharmaceutical Design C-Type Lectins on Dendritic Cells and Their Interaction with Pathogen-Derived and Endogenous Glycoconjugates
Current Protein & Peptide Science The Immunomodulation and Anti-Inflammatory Effects of Garlic Organosulfur Compounds in Cancer Chemoprevention
Anti-Cancer Agents in Medicinal Chemistry Unveiling the Transient Protein-Protein Interactions that Regulate the Activity of Human Lemur Tyrosine Kinase-3 (LMTK3) Domain by Cyclin Dependent Kinase 5 (CDK5) in Breast Cancer: An in silico Study
Current Proteomics An Emerging Therapeutic Approach by Targeting Myoferlin (MYOF) for Malignant Tumors
Current Topics in Medicinal Chemistry Genetics of the First Seven Proprotein Convertase Enzymes in Health and Disease
Current Genomics Plant Natural Products in Anticancer Drug Discovery
Current Organic Chemistry Anticancer Potential of Mefenamic Acid Derivatives with Platelet-Derived Growth Factor Inhibitory Property
Anti-Cancer Agents in Medicinal Chemistry Glycogen Synthase Kinase-3 Beta; A New Target in Pancreatic Cancer?
Current Cancer Drug Targets ANTI-ADHESION Evolves To a Promising Therapeutic Concept in Oncology
Current Medicinal Chemistry Diabetes-specific Modulation of Peripheral Blood Gene Expression Signatures in Colorectal Cancer
Current Molecular Medicine The Mutator Phenotype in Cancer: Molecular Mechanisms and Targeting Strategies
Current Drug Targets Inhibition of TGF- Signaling for the Treatment of Tumor Metastasis and Fibrotic Diseases
Current Signal Transduction Therapy Antibodies and their Multivalent Constructs for Cancer Therapy
Protein & Peptide Letters Nanoparticle-Based Tumor Theranostics with Molecular Imaging
Current Pharmaceutical Biotechnology Alkaloid-Metal Based Anticancer Agents
Current Topics in Medicinal Chemistry Protein Tyrosine Phosphatases, New Targets for Cancer Therapy
Current Cancer Drug Targets