An inhibitor of ALK5 (TGFBR1)
GW788388 is a selective inhibitor of ALK5 with IC50 value of 18 nM [1].
Transforming growth factor beta (TGF-beta) type I receptor (ALK5) is the receptor of TGF-beta and plays an important role in transducing the TGF-beta signal from the cell surface to the cytoplasm [2 ].
GW788388 is a potent TGF-beta type I receptor inhibitor and has a much improved pharmacokinetic profile compared with the reported TGF-beta type I receptor inhibitor SB431542. When tested with human embryonic kidney 293T cells transfected with ALK5, TβRII, BMPRII or ActRII, GW788388 exhibited specific inhibitory function on the autophosphorylation of ALK5 and TβRII, while had some extent to ActRII and had no effect on BMPRII. Further, using Namrumurine mammary gland (NMuMG), MDA-MB-231, renal cell carcinoma (RCC)4 and U2OS cell lines, GW788388 treatment inhibited TGF-β-induced Smad2 phosphorylation, inhibited TGF-β-induced EMT and growth, and TGF-β-induced fibrotic responses [1]. In ESCC/fibroblast/HMVEC co-culture model, GW788388 treatment (1 μM) resulted in a complete reversal of vascular network formation that indicated GW788388 blocked ESCC-induced neoangiogenesis [3].
In 6-month-old db/db mouse model of spontaneous diabetic nephropathy, administration of GW788388 at the dose of 2 mg/kg/day orally for 5 weeks attenuated renal fibrosis without any side-effect [1]. In 10-week Sprague-Dawley rats model, oral administration of GW788388 (100-1000 mg/kg/day) for 4 days induced the thickness of femoral physis in a dose-dependent manner and severity of physeal changes , as well as subphyseal hyperostosis, increased with duration of dosing progressing from minimal to moderate in rats given 300 mg/kg/day for 10 days [2].
参考文献:
[1].? Petersen, M., et al., Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int, 2008. 73(6): p. 705-15.
[2].? Frazier, K., et al., Inhibition of ALK5 signaling induces physeal dysplasia in rats. Toxicol Pathol, 2007. 35(2): p. 284-95.
[3].? Noma, K., et al., The essential role of fibroblasts in esophageal squamous cell carcinoma-induced angiogenesis. Gastroenterology, 2008. 134(7): p. 1981-93.
| Cell experiment [1]: | |
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Cell lines |
NMuMG and MDA-MD-231 cells |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months. |
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Reaction Conditions |
1, 2.5, 5 or 10 μM; 1 hr |
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Applications |
In NMuMG and MDA-MD-231 cells, GW788388 dose-dependently inhibited TGF-β-induced Smad2 phosphorylation. In addition, TGF-β-mediated Smad1/5 phosphorylation, which requires ALK5 and TbRII, was also inhibited by GW788388. |
| Animal experiment [1]: | |
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Animal models |
A db/db mouse model of spontaneous diabetic nephropathy |
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Dosage form |
2 mg/kg/day; p.o.; for 5 weeks |
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Applications |
In a db/db mouse model of spontaneous diabetic nephropathy, GW788388 significantly reduced collagen deposits, substantially improved glomerulopathy (marked by mesangial matrix expansion, mesangial hypertrophy, proliferation, and glomerular basement membrane thickening), as well as decreased urinary albumin concentrations. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1]. Petersen, M., et al., Oral administration of GW788388, an inhibitor of TGF-beta type I and II receptor kinases, decreases renal fibrosis. Kidney Int, 2008. 73(6): p. 705-15. |
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