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lüll SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7 DaCosta Byfield S; Major C; Laping NJ; Roberts ABMol Pharmacol 2004[Mar]; 65 (3): 744-52Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-beta) and/or modulate effects of TGF-beta in normal responses. Inhibition of TGF-beta signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-beta signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride (SB-505124), a member of a new class of small molecule inhibitors related to imidazole inhibitors of p38, which inhibit the TGF-beta type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. We demonstrate that this compound selectively and concentration-dependently inhibits ALK4-, ALK5-, and ALK 7-dependent activation of downstream cytoplasmic signal transducers, Smad2 and Smad3, and of TGF-beta-induced mitogen-activated protein kinase pathway components but does not alter ALK1, ALK2, ALK3 or ALK6-induced Smad signaling. SB-505124 also blocks more complex endpoints of TGF-beta action, as evidenced by its ability to abrogate cell death caused by TGF-beta1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542.|*Proteins[MESH]|Activin Receptors, Type I/*antagonists & inhibitors[MESH]|Activins/pharmacology[MESH]|Animals[MESH]|Benzamides/pharmacology[MESH]|COS Cells[MESH]|Cell Death/drug effects[MESH]|DNA-Binding Proteins/metabolism[MESH]|Dioxoles/pharmacology[MESH]|Drug Interactions[MESH]|Genes, Reporter[MESH]|Humans[MESH]|Mitogen-Activated Protein Kinases/metabolism[MESH]|Protein Serine-Threonine Kinases[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/*antagonists & inhibitors[MESH]|Smad Proteins[MESH]|Trans-Activators/metabolism[MESH]|Transforming Growth Factor beta/*antagonists & inhibitors[MESH]|Tumor Cells, Cultured[MESH] |