SB-525334

Biological Activity

SB-525334 is a potent and selective inhibitor of the transforming growth factor-beta1 (TGF-beta1) receptor, activin receptor-like kinase (ALK5). In cell-based assays, SB-525334 (1 microM) blocked TGF-beta1-induced phosphorylation and nuclear translocation of Smad2/3 in renal proximal tubule cells and inhibited TGF-beta1-induced increases in plasminogen activator inhibitor-1 (PAI-1) and procollagen alpha1(I) mRNA expression in A498 renal epithelial carcinoma cells. SB-525334 inhibited ALK5 kinase activity with an IC50 of 14.3 nM and was approximately 4-fold less potent as an inhibitor of ALK4 with IC50 of 58.5 nM. SB-525334 significantly increased apoptotic cell death in gemcitabine-resistant cells. SB-525334 reverses pulmonary arterial pressure and inhibits right ventricular hypertrophy in a rat model of PAH effectively. SB-525334 treatment showed significant attenuation in Smad2/3 nuclear translocation, decrease in CTGF-expressing cells, myofibroblast proliferation and type I collagen deposition.

Product Citations

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  Cancer Biother Radiopharm. 2020 Mar;35(2):120-128.

  Activation of TGF-β1 Pathway by SCUBE3 Regulates TWIST1 Expression and Promotes Breast Cancer Progression.
  SB-525334 purchased from AbMole

• 

  J Cell Physiol. 2019 Jun;234(6):9698-9710.

  H19/miR-148a/USP4 axis facilitates liver fibrosis by enhancing TGF-β signaling in both hepatic stellate cells and hepatocytes.
  SB-525334 purchased from AbMole

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  Oncol Lett. 2018 Dec 10.

  Pancreatic stellate cells facilitate pancreatic cancer cell viability and invasion.
  SB-525334 purchased from AbMole

Customer Product Validations & Biological Datas

	Source	Am J Physiol Renal Physiol (2015). Figure 4. SB-525334
	Method	Endothelial function
	Cell Lines	rats
	Concentrations	-
	Incubation Time	24-h
	Results	Aortic endothelial cell lysates obtained from the four groups of rats on day 7 of the experiment demonstrated activation of ALK5 by HS intake as well as the anticipated inhibition of ALK5 by SB-525334

Chemical Information

Molecular Weight	343.42
Formula	C21H21N5
CAS Number	356559-20-1
Solubility (25°C)	DMSO 60 mg/mL Ethanol 40 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Thomas M, et al. Am J Pathol. Activin-like kinase 5 (ALK5) mediates abnormal proliferation of vascular smooth muscle cells from patients with familial pulmonary arterial hypertension and is involved in the progression of experimental pulmonary arterial hypertension induced by monocrotaline.

[2] Laping NJ, et al. Clin Cancer Res. Tumor-specific efficacy of transforming growth factor-beta RI inhibition in Eker rats.

[3] Higashiyama H, et al. Exp Mol Pathol. Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis.

[4] Grygielko ET, et al. J Pharmacol Exp Ther. Inhibition of gene markers of fibrosis with a novel inhibitor of transforming growth factor-beta type I receptor kinase in puromycin-induced nephritis.