SB-505124

SB-505124 is a selective inhibitor of?TGF-β Receptor type I receptors (ALK4, ALK5, ALK7), with?IC₅₀s?of 129 nM and 47 nM for?ALK4, ALK5, respectively, but it does not inhibit ALK1, 2, 3, or 6. IC50 & Target: IC50: 129 nM (ALK4), 47 nM (ALK5) In Vitro: SB-505124 demonstrates no toxicity to renal epithelial A498 cells at concentrations up to 100 μM for 48 h. 505124 inhibits the closely related ALK4 with an IC₅₀ value of 129±11 nM (about 2.5-fold less sensitive than ALK5) but does not inhibit ALK2 at concentrations up to 10 μM. SB-505124 (1 μM) inhibits the TGF-β-induced phosphorylation of Smad2 in all three of these cell lines in a concentration-dependent fashion. SB-505124 (1 or 5 μM) potently inhibits TGF-β-induced activation of JNK/SAP, extracellular signal-regulated kinase 1/2, and p38 despite the different patterns of activation in these cells^[1]. SB-505124 (10 μM) impairs Smad2 phosphorylation and CTGF and α-SMA expression in vitro^[2]. SB-505124 susspresses CTGF and α-SMA observed by immunofluorescence. Cell outgrowth from explants dissected from eyes to which SB-505124 is applied during GFS is robust while outgrowth is poor from those treated with MMC^[3]. In Vivo: SB-505124 (5 mg/kg; i.p.) alone has no effect in C57Bl6 mice with A549 xenografts, but administration of SB-505124 with a single dose of Carboplatin (60 mg/kg) results in durable responses without the need for maintenance therapy in five animals^[4].