生物活性

• 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^[3]. SB-431542 is a selective ALK5 inhibitor with IC50 value of 94nM (measured by GST-ALK5 kinase activity)^[1]. SB-431542 also shows inhibition against ALK4 and ALK7, which are very similar to ALK5 in their kinase domains. Addition of SB-431542 for 24h at a concentration of 10uM can efficiently inhibit the p-Smad2 phosphorylated by activated ALK4, ALK5, and ALK7 in NIH 3T3 cells, with no effect on BMP induced phosphorylation of Smad1, which is mediated by ALKs 2, 3, and 6. The transcription activity mediated by the activated endogenous ALKs 4, 5 and 7 can also inhibited dose-dependently by 0.25, 0.5, 0.75, 1, 2, 5, or 10uM SB-431542^[2]. SB-431542 has performance in both reprogramming and differentiation, as 1. SB-431542 can replace SOX2 in the reprogramming of mouse fibroblasts to iPSCs; 2. Combined with PD0325901 and Thiazovivin, SB-431542 can increase the efficiency of reprogramming human somatic cells to iPSCs; 3. SB-431542, combined with CHIR99021, ISX-9, Forskolin and I-BET151, can direct lineage reprogramming of fibroblasts to mature neurons; 4. SB-431542, in combination with either LDN193189 or Noggin, promotes the differentiation of NPCs from human PSCs; 5. SB-431542 can promote the proliferation and sheet formation of mouse ES-derived endothelial cells; 6. SB-431542 can enhance differentiation of cardiomyocytes.
• 作用机制SB-431542 acts as a competitive ATP binding site kinase inhibitor^[2].

• 动物研究
  剂量	Mice (i.p.): 4.2 mg/kg[4], 10 mg/kg[5]; rat: 2.1 mg/kg[6] (s.c.)
  给药途径	i.p., s.c.