LY-364947

LY-364947 (HTS466284) is a potent ATP-competitive inhibitor of TGFβR-I with IC₅₀ of 59 nM, and exhibits 7-fold selectivity over TGFβR-II^[1]. IC50 & Target: IC50: 59 nM (TGFβR-I) In Vitro: LY-364947 is an ATP competitive and tight-binding inhibitor, inhibiting phosphorylation of P-Smad3 by TGFβR-I Kinase with K_i of 28 nM. LY-364947 inhibits in vivo Smad2 phosphorylation within the NMuMg cells with IC₅₀ of 135 nM. LY-364947 reverses TGF-β-mediated growth inhibition in NMuMg cells with IC₅₀ of 0.218 μM. LY-364947 potentiates the xVent2-lux BMP4 response in NMuMg cells by 30% at concentrations as low as 0.25 μM. LY-364947 (2 μM) prevents TGF-β-induced epithelial−mesenchymal transition in NMuMg cells^[1]. LY-364947 (3 μM) induces expression of Prox1 and LYVE-1 in almost all HDLECs after 24 hours^[2]. LY-364947 promotes nuclear export of Foxo3a, with low Smad2/3 and high Akt phosphorylation levels in leukaemia-initiating cells. LY-364947 (< 20 μM) suppresses leukaemia-initiating cells colony-forming ability after co-culture with OP-9 stromal cells^[3]. In Vivo: LY-364947 (1 mg/kg, i.p.) accelerates lymphangiogenesis, as evidence by significantly increasing the LYVE-1-positive areas in a mouse model of chronic peritonitis. LY-364947 (1 mg/kg, i.p.) significantly increases the LYVE-1-positive areas in tumor tissues in tumor xenograft models using BxPC3 pancreatic adenocarcinoma cells^[2]. LY-364947 (25 mg/kg) increases p-Akt and decreases nuclear Foxo3a in leukaemia-initiating cells in CML-affected mice^[3].