6-[2-tert-Butyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-quinoxaline

SB525334 is a potent and selective inhibitor of TGFβ receptor I (ALK5) with IC50 of 14.3 nM in a cell-free assay, 4-fold less potent to ALK4 than ALK5 and inactive to ALK2, 3, and 6.

SB 525334 shows no inhibition in the enzymes ALK2, 3, and 6, with IC50 values > 10 μM. SB 525334 blocks phosphorylation induced by TGF-β1 and nuclear translocation of Smad2/3 in renal proximal tubule cells. SB 525334 also inhibits the increased mRNA expression levels of plasminogen activator inhibitor-1 (PAI-1) and procollagen α1(I) induced by TGF-β1 in A498 renal epithelial carcinoma cells at 1 μM). SB 525334 (1 μM) attenuates the heightened sensitivity to TGF-β1 exhibited by pulmonary artery smooth muscle cells (PASMCs) from patients with familial forms of idiopathic pulmonary arterial hypertension (PAH).

SB 525334 (10 mg/kg/day) decreases the renal mRNA levels of PAI-1, procollagen α1(I), and procollagen α1(III) in a nephritis-induced renal fibrosis rat model. Furthermore, PAN-induced proteinuria is significantly inhibited by SB 525334 (10 mg/kg/day). SB 525334 may also be efficacious in mesenchymal tumors. SB 525334 (10 mg/kg/day) significantly decreases uterine mesenchymal tumor incidence, multiplicity, and size in Eker rats. SB 525334 significantly reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH. This is revealed by a significant reduction in pulmonary arteriole muscularization induced by monocrotaline (used to induce PAH) after treatment with SB 525334 (3 or 30 mg/kg). In a Bleomycin-induced pulmonary fibrosis mice model, SB 525334 (10 mg/kg or 30 mg/kg) attenuates the histopathological alterations in the lung, and significantly decreased mRNA expression of Type I and III procollagen and fibronectin. SB 525334 also attenuates Smad2/3 nuclear translocation, myofibroblast proliferation, deposition of Type I collagen, and decreases CTGF-expressing cells.

http://www.selleckchem.com/products/SB-525334.html

SB-525334 is a potent inhibitor of the TGF-β receptor 1 (TGF-β R1, ALK5) kinase (IC₅₀ = 14.36 nM). It is ~4-fold less effective against ALK4 and inactive against ALK2, ALK3, and ALK6. SB-525334 blocks TGF-β1-induced phosphorylation and nuclear translocation of SMAD2/3 as well as TGF-β1-directed gene expression. It is effective in vivo, preventing puromycin aminonucleoside-induced renal fibrosis and bleomycin-induced pulmonary fibrosis. SB-525334 also modulates carcinogenesis and suppresses the development of pulmonary arterial hypertension in animals.

SB-525334 is a potent activin receptor-like kinase (ALK5)/ type I TGFβ-receptor kinase inhibitor with IC50 = 14.3 nM.

SB-525334 was used to study TGFβ1-mediated human trophoblast differentiation.⁷

ChEBI: 6-[2-tert-butyl-5-(6-methyl-2-pyridinyl)-1H-imidazol-4-yl]quinoxaline is a quinoxaline derivative.

Selective inhibitor of transforming growth factor- β receptor I (ALK5, TGF- β RI) (IC 50 = 14.3 nM). Inhibits TGF- β 1-induced smad2/3 nuclear localisation and TGF- β 1-induced mRNA expression in kidney cells. Attenuates bleomycin-induced pulmonary fibrosis.

SB-525334 is a potent activin receptor-like kinase (ALK5)/ type I TGFβ-receptor kinase inhibitor with IC50 = 14.3 nM.

Store at -20°C

The small-molecule SB-525334 inhibits transforming growth factor-β1 receptor with an IC50 of 14.3 nM. SB-525334 also inhibits the related receptor ALK4 but is inactive against ALK2, ALK3, and ALK6. Inhibition of TGF-β downstream signaling by SB-525334 blocks phosphorylation and nuclear translocation of Smad2/3 protein and reduces PAI-1 and procollagen α1(I) mRNA expression in renal epithelial carcinoma cells. SB-525334 treatment of a bleomycin-induced pulmonary fibrosis model reduced TGF-β-mediated nuclear translocation of Smad2/3, decreased myofibroblast proliferation, and attenuated pulmonary fibrosis. Exposure of mesenchymal and epithelial tumors in Eker rats to SB-525334 reduced the size and number of mesenchymal tumors but had the opposite effect on epithelial cancer cells and lesions. Inhibition of ALK5 by SB-525334 in both human pulmonary artery smooth muscle cells and a rat model of pulmonary arterial hypertension resulted in decreased sensitivity to TGF-β, and attenuated pulmonary arterial pressure and right ventricular hypertrophy.

[1] EUGENE T GRYGIELKO. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis.[J]. Journal of Pharmacology and Experimental Therapeutics, 2005, 313 3: 943-951. DOI:10.1124/jpet.104.082099
[2] HIROYUKI HIGASHIYAMA . Inhibition of activin receptor-like kinase 5 attenuates Bleomycin-induced pulmonary fibrosis[J]. Experimental and molecular pathology, 2007, 83 1: Pages 39-46. DOI:10.1016/j.yexmp.2006.12.003
[3] YEON JEONG KIM. Transforming growth factor beta receptor I inhibitor sensitizes drug-resistant pancreatic cancer cells to gemcitabine.[J]. Anticancer research, 2012, 32 3: 799-806.