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
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
-
Impact of New Technologies on Pharmacogenomics
Current Pharmacogenomics and Personalized Medicine Omega-3 Polyunsaturated Fatty Acids and Cancer
Anti-Cancer Agents in Medicinal Chemistry The Synergistic Effect of Humanized Monoclonal Antibodies Targeting Insulin-Like Growth Factor 1 Receptor (IGF-1R) and Chemotherapy
Current Drug Targets Immunomodulation Mechanism of Antidepressants: Interactions between Serotonin/Norepinephrine Balance and Th1/Th2 Balance
Current Neuropharmacology Targeting p73 - a Potential Approach in Cancer Treatment
Current Pharmaceutical Design Aptamer-Mediated Cancer Gene Therapy
Current Gene Therapy Hereditary Breast Cancer in Sub-Saharan Africa
Current Women`s Health Reviews Synthesis of New Curcumin-like Pentadienones by O- and C-glycosylation
Current Organic Chemistry Foods for Health and to Treat Diseases
Current Pediatric Reviews Important Anti-Cancer Applications of Protein Based Nanoparticles
Current Proteomics Pleiotropic Effects of Statins: Untapped Potential for Statin Pharmacotherapy
Current Vascular Pharmacology The Adiponectin Signaling Pathway as a Novel Pharmacological Target
Mini-Reviews in Medicinal Chemistry Intraoperative Targeted Optical Imaging: A Guide towards Tumor-Free Margins in Cancer Surgery
Current Pharmaceutical Biotechnology Harnessing Polypharmacology with Computer-Aided Drug Design and Systems Biology
Current Pharmaceutical Design Insulin-Like Growth Factor 2 - The Oncogene and its Accomplices
Current Pharmaceutical Design Exosomal microRNAs as Potentially Useful Tools in Cancer Biomarker Discovery
Recent Patents on Biomarkers Targeting Poly (ADP) Ribose Polymerase I (PARP-1) and PARP-1 Interacting Proteins for Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry Epithelial Mesenchymal Transition and Cancer Stem Cell-Like Phenotypes Facilitate Chemoresistance in Recurrent Ovarian Cancer
Current Cancer Drug Targets Synthesis, Radiosynthesis and Metabolism of 131I-Y-c(CGRRAGGSC)
Anti-Cancer Agents in Medicinal Chemistry Cancer-Type Organic Anion Transporting Polypeptide 1B3: Current Knowledge of the Gene Structure, Expression Profile, Functional Implications and Future Perspectives
Current Drug Metabolism