LY364947

Transforming growth factor-β (TGF-β) signals through a cell surface heteromeric complex involving type I (TGF-β RI) and type II (TGF-β RII) receptors. Downstream signal transduction is mediated by the TGF-β RI kinase domain through the phosphorylation of Smad proteins. LY364947 is a selective inhibitor of TGF-β RI (TGFR-I, TβR-I, ALK-5), with an IC₅₀ value of 59 nM.¹ LY364947 less effectively inhibits TGF-β RII (IC₅₀ = 400 nM), p38 MAPK (IC₅₀ = 740 nM), and mixed-lineage kinase 7 (MLK7; IC₅₀ = 1,400 nM).^1,2 It inhibits TGF-β-induced cell growth (IC₅₀ = 89 nM) in NIH 3T3 mouse fibroblasts¹ and TGF-β-directed Smad phosphorylation, synthesis of fibronectin, PAI-1 and uPA protein, and matrigel invasion in MDA-MB-231 cells.³

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1. Sawyer, J.S., Anderson, B.D., Beight, D.W., et al. Synthesis and activity of new aryl- and heteroaryl-substituted pyrazoleInhibitors of the transforming growth factor-b type I receptor kinase domain. J. Med. Chem. 46(19), 3953-3956 (2003).

2. Li, H.y., Wang, Y., Heap, C.R., et al. Dihydropyrrolopyrazole transforming growth factor-b type I receptor kinase domain inhibitors: A novel benzimidazole series with selectivity versus transforming growth factor-b type II receptor kinase and mixed lineage kinase-7. J. Med. Chem. 49(6), 2138-2142 (2006).

3. Shiou, S.R., Datta, P.K., Dhawan, P., et al. Smad4-dependent regulation of urokinase plasminogen activator secretion and RNA stability associated with invasiveness by autocrine and paracrine transforming growth facto. The Journal of Biological Chemisty 281(45), 33971-33981 (2006).