ChemicalBook Product Catalog Biochemical Engineering Inhibitors TGF-beta / Smad TGF-beta / Smad inhibitors GW788388

GW788388

Product NameGW788388
CAS452342-67-5
MFC25H23N5O2
MW425.48
EINECS
MOL File452342-67-5.mol

Chemical Properties

Density	1.34
storage temp.	2-8°C
solubility	Soluble in DMSO (18 mg/ml with warming)
form	solid
color	Off-white
Stability	Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.

Usage And Synthesis

Description

GW 788388 is a selective inhibitor of transforming growth factor-β (TGF-β) type 1 receptor (TGFBR1 or ALK5; IC₅₀ = 18 nM). It inhibits the expression of collagen type I in cells (IC₅₀ = 93 nM) and in mice when given orally at 10 mg/kg once a day. As TGF-β stimulates fibrosis in a range of tissues, GW 788388 reduces typical features of fibrosis, including tissue remodeling, increased expression of α-smooth muscle actin and production of collagen I. GW 788388 also blocks TGF-β-mediated production of VEGF by fibroblasts, as well as subsequent angiogenesis in vitro. Inhibition of ALK5 signaling by GW 788388 also induces hypertrophy in femoral growth plates in rats.

Uses

GW788388 is a new TGF-beta type I receptor inhibitor with a much improved pharmacokinetic profile compared with SB431542.

in vivo

GW788388 given orally for 5 weeks significantly reduces renal fibrosis and decreased the mRNA levels of key mediators of extracellular matrix deposition in kidneys in db/db mice^[1]. GW788388 (50 mg/kg/day, p.o.) significantly attenuates systolic dysfunction in the MI animals, together with the attenuation of the activated (phosphorylated) Smad2 (P < 0.01), α-smooth muscle actin (P < 0.001), and collagen I (P < 0.05) in the noninfarct zone of MI rats^[2]. GW788388 reduces the expression of collagen IA1 by 80% at a dose of 1 mg/kg twice a day (b.i.d.). GW788388 significantly reduces the expression of collagen IA1 mRNA when administered orally at 10 mg/kg once a day (u.i.d.) in a model of puromycin aminonucleoside-induced renal fibrosis^[3].

storage

Store at +4°C

References

[1] FRANÇOISE GELLIBERT. Discovery of 4-{4-[3-(Pyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2-yl}-N-(tetrahydro-2H- pyran-4-yl)benzamide (GW788388): A Potent, Selective, and Orally Active Transforming Growth Factor-β Type I Receptor Inhibitor[J]. Journal of Medicinal Chemistry, 2006, 49 7: 2210-2221. DOI:10.1021/jm0509905
[2] M. PETERSEN . Oral administration of GW788388, an inhibitor of TGF-β type I and II receptor kinases, decreases renal fibrosis[J]. Kidney international, 2008, 73 6: Pages 705-715. DOI:10.1038/sj.ki.5002717
[3] FABIANE L DE OLIVEIRA. Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease.[J]. PLoS Neglected Tropical Diseases, 2012: e1696. DOI:10.1371/journal.pntd.0001696
[4] KAZUHIRO NOMA . The Essential Role of Fibroblasts in Esophageal Squamous Cell Carcinoma–Induced Angiogenesis[J]. Gastroenterology, 2008, 134 7: Pages 1981-1993. DOI:10.1053/j.gastro.2008.02.061
[5] YUNMEE LHO. Effects of TGF-β1 Receptor Inhibitor GW788388 on the Epithelial to Mesenchymal Transition of Peritoneal Mesothelial Cells.[J]. International Journal of Molecular Sciences, 2021, 22 9. DOI:10.3390/ijms22094739

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