生物活性

• 靶点	TGFβR1 IC50:56nM

• 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 translocate into the nucleus and regulate the expression of TGF-β target genes^[1]. LY2157299 (Galunisertib) is a selective TGF-β1 Type I receptor inhibitor with IC50 values of 0.17, 0.21 and 0.08 nM for TGF-βRI, TGF-βRII and ALK4 (measure by kinase assays)^[2] Pre-treatment with 0.5 μM LY2157299 for 1h can abolish or reduce SMAD2 phosphorylation induced by TGF-β-activated TBRI in HS-5 and K562 cells. After 14 days of oral administration of LY-2157299, 100 mg/kg, daily, anemia in a model of bone marrow failure was improved. LY-2157299 can result in a significant increase in erythroid and myeloid colony numbers in all patients, which pointed to a high therapeutic potential of TβRI inhibition by LY2157299 in low-grade MDS^[3]. Orally administered with LY2157299 (75 mg/kg, bid) significantly suppress growth of transplanted tumors in B16 cells xenograft mice^[4]. Up to now, a phase 3 study of LY2157299 treatment for Myelodysplastic Syndromes, as well as phase 2 studies of LY2157299 treatment for glioma has been completed. The phase 2 studies of LY2157299 treatment for solid tumor, non-small cell lung cancer recurrent and hepatocellular carcinoma recurrent are recruiting (see https://www.clinicaltrials.gov/).
• 作用机制LY2157299 binds to the ATP-binding site of TGFβRI.

• 动物研究
  剂量	Mice[6] (p.o.): 150 mg/kg, 1.5 mg/kg (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Nude mice[7] Dose 75 mg/kg Administration p.o. VT/F 2.02 ± 0.11 L V/F 0.64 ± 0.58 L CLD/F 1.05 ± 0.33 L/h Cl/F 0.57 ± 0.08 L/h