Protein kinase inhibitors in the treatment of pulmonary fibrosis.
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.
Department of Medicinal Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Sylvie
S
Garneau-Tsodikova
Victor J
VJ
Thannickal
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt