生物活性

• 靶点

  TGFβR1 Ki:38nM

  TGFβR2 Ki:300nM

• 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]. LY2109761 is a dual inhibitor of TGF-βRI and TGF-βRII with Ki values of 38 and 300nM (measured by in vitro kinase assay). Pre-treatment with LY2109761 of 5uM concentration for 24h (serum free) can abolish the p-smad2 induced by TGF-β receptor which activated by TGF-β/serum in the following 30min in L3.6pl/GLT cells. Inhibition of TGF-βRI/II pathway with LY2109761 (5uM) significantly enhanced the anoikis in L3.6pl/GLT cells for 8h. LY2109761 of 5uM for 48-hour treatment can abolish the TGF-β1–stimulated migration and invasiveness of L3.6pl/GLT cells, the metastatic variant of pancreatic cancer cells. 50mg/kg of LY2109761 orally given to mice twice a day, 5 days per week for 4 weeks, shows antimetastatic effect in pancreatic cancer cell spontaneous metastasis models^[1]. The invasiveness of the embryonic chicken vasculature by HLE tumors were decreased with treatment of 0.1uM LY2109761 for 48h, showing that LY2109761 can inhibit HLE tumors invading stroma and blood vessels^[3].
• 作用机制LY2109761 binds to the ATP binding site of the TGF-β R1 kinase domain. ^[4]

• 动物研究
  剂量	Mice: 50 mg/kg - 100 mg/kg[5] (p.o.)
  给药途径	p.o.