生物活性

• 靶点	TGFβR1 IC50:59nM

• 描述The TGF-β pathway regulates a wide variety of cellular processes in many different cell types and biological contexts. There are three identified TGF receptor ligands, TGF-β1, 2 and 3. Activated TGF-β ligands can interact with TGF-β type II receptors (TβRII), then recruit and phosphorylate the TGF-β type I receptors (also called as TβRI or ALK5). In turn, activated TβRI phosphorylates SMAD2 and SMAD3 at C-terminal serine residues. Following that, phosphorylated SMAD and SMAD3 assemble into heterodimeric and trimeric complexes with SMAD4. Then the trimeric complex translocates into the nucleus and regulates the expression of TGF-β target genes^[2]. LY364947 is a multiple inhibitor with IC50 values of 0.059, 0.4, 1.4uM for TGF-βRI, TGF-βRII and MLK-7, respectively (measured by kinase activity)^[1]. Addition of 400nM LY364947 for 24h can block the Smad phosphorylation induced by exogenous TGFβ1 in U251, U87MG and GL261 glioma cell lines. Pre-treatment with 400nM LY364947 for24 hours before radiation exposure could significantly increase the radio sensitivity in all the three cell lines, accompanied with the decreased radiation-induced phosphorylation of ATM Ser-1981 and P53-Ser15 as well as fewer γH2AX foci, a marker of DNA damage response. These indicated that TGFβ inhibition by LY364947 could abrogate the response to DNA damage and increase radio sensitivity in glioma cells^[3]. Treatment with 2µM LY364947 for 24h can prevent TGF-β-induced epithelial-mesenchymal transition in NMuMg cells^[4].
• 作用机制LY364947 is an ATP competitive inhibitor of the TGFβ type I receptor.^[4]

• 动物研究
  剂量	Mice (i.p.): 10 mg/kg[5], 1 mg/kg[6]
  给药途径	i.p.