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GW788388
本产品不向个人销售,仅用作科学研究,不用于任何人体实验及非科研性质的动物实验。
GW788388图片
CAS NO:452342-67-5
规格:≥98%
包装与价格:
包装价格(元)
5mg电议
10mg电议
25mg电议
50mg电议
100mg电议
250mg电议
500mg电议

产品介绍
GW788388 (GW-788388; GW 788388) is an inhibitor of ALK5/TGF-β type II receptor with potential antifibrotic activity. It inhibits ALK5/TGF-β type II receptor with an IC50 of 18 nM in a cell-free assay.
理化性质和储存条件
Molecular Weight (MW)425.48
FormulaC25H23N5O2
CAS No.452342-67-5
Storage-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)DMSO: 15 mg/mL (35.3 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)30% PEG400+0.5% Tween80+5% Propylene glycol: 30 mg/mL
SynonymsGW788388; GW-788388; GW 788388
实验参考方法
In Vitro

In vitro activity: GW788388 shows anti-TGF-β activity with IC50 of 93 nM in cellular assay. GW788388 shows some inhibitory to activin type II receptor (ActRII) but no inhibitory to bone morphogenic protein (BMP) type II receptor. GW788388 shows no toxicity in Namru murine mammary gland (NMuMG), MDA-MB-231, renal cell carcinoma (RCC)4, and U2OS cells at 4 nM to 15 μM. GW788388 blocks TGF-β-induced Smad activation and target gene expression, while decreasing epithelial-mesenchymal transitions and fibrogenesis. GW788388 inhibits ALK5, ALK4, ALK7 and TGF-β-mediated growth arrest.


Kinase Assay: GW788388 binding to ALK5 is tested on purified recombinant GST–ALK5 (residues 198-503). Displacement of rhodamine green fluorescently labeled ATP competitive inhibitor by different concentrations of GW788388 is used to calculate a binding pIC50. GST–ALK5 is added to a buffer containing 62.5 mM N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid (Hepes), pH 7.5, 1 mM dithiothreitol (DTT), 12.5 mM MgCl2, 1.25 mM 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS), and 1 nM rhodamine green-labeled ligand so that the final ALK5 concentration is 10 nM based on active-site titration of the enzyme. The enzyme/ligand reagent (40 μL) is added to 384-well assay plates containing 1 μL of different concentrations of GW788388. The plates are read immediately on a LJL Acquest fluorescence reader with excitation, emission, and dichroic filters of 485, 530, and 505 nm, respectively. The fluorescence polarization for each well is calculated by the Acquest and is then imported into curve-fitting software for construction of concentration–response curves.


Cell Assay: Cell viability/proliferation assays (Namru murine mammary gland (NMuMG), MDA-MB-231, renal cell carcinoma (RCC)4, and U2OS cells) are done according to the manufactures instructions (CellTiter 96 Aqueous One Solution Cell Proliferation Assay). Viability and proliferation are measured after 72 hours GW788388 treatment in the presence or absence of TGF-β.

In VivoGW788388 exhibits an adequate pharmacokinetic profile in rats (plasma clearance less than 40 mL/min/kg and half-life more than 2 hours). GW788388 significantly reduces the expression of collagen IA1 mRNA by 80% in a model of puromycin aminonucleoside-induced renal fibrosis at 10 mg/kg. GW788388 attenuates TGF-β signalling and effectively reduces hallmarks of fibrogenesis in mice suffering from late-stage diabetic nephropathy at 2 mg/kg. Treatment with GW788388 significantly attenuates systolic dysfunction in the myocardial infarction (MI) animals, together with the attenuation of the activated (phosphorylated) Smad2, α-smooth muscle actin, and collagen I in the noninfarct zone of MI rats. Cardiomyocyte hypertrophy in MI hearts is also attenuated by GW788388 inhibition. GW788388 reduces the fibrotic response in bleomycin-injected animals at 2 mg/kg.
Animal modelSprague-Dawley rats with dimethylnitrosamine- (DMN-) induced liver disease or puromycin aminonucleoside-induced renal fibrosis
Formulation & DosageDissolved in 4% DMSO and 96% [0.5% HPMC/5% Tween/20%HCl (1 M) in NaH2PO4 (0.1 M); 3 or 10 mg/kg; oral administration
References

J Med Chem. 2006 Apr 6;49(7):2210-21; Kidney Int. 2008 Mar;73(6):705-15.