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

• 

  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

• 

  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

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

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.

Chemical Information

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.