SB-505124 Is a Selective Inhibitor of Transforming Growth Factor-β Type I Receptors ALK4, ALK5, and ALK7 (original) (raw)
Research ArticleArticle
Molecular Pharmacology March 2004, 65 (3) 744-752; DOI: https://doi.org/10.1124/mol.65.3.744
Abstract
Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-β) and/or modulate effects of TGF-β in normal responses. Inhibition of TGF-β signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-β 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-β 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-β–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-β action, as evidenced by its ability to abrogate cell death caused by TGF-β1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542.
- Received June 13, 2003.
- Accepted December 12, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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