PT - JOURNAL ARTICLE AU - Stacey DaCosta Byfield AU - Christopher Major AU - Nicholas J. Laping AU - Anita B. Roberts TI - SB-505124 Is a Selective Inhibitor of Transforming Growth Factor-β Type I Receptors ALK4, ALK5, and ALK7 AID - 10.1124/mol.65.3.744 DP - 2004 Mar 01 TA - Molecular Pharmacology PG - 744--752 VI - 65 IP - 3 4099 - http://molpharm.aspetjournals.org/content/65/3/744.short 4100 - http://molpharm.aspetjournals.org/content/65/3/744.full SO - Mol Pharmacol2004 Mar 01; 65 AB - 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.