A-83-01 Chemical Properties

Melting point:

111℃

Boiling point:

590.0±60.0 °C(Predicted)

Density 

1.27±0.1 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

DMSO: soluble5mg/mL, clear (warmed)

form 

powder

pka

8.77±0.70(Predicted)

color 

white to beige

Stability:

Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 2 months.

Safety Information

Hazard Codes 

Xn

Risk Statements 

22-36/37/38

Safety Statements 

26-36

WGK Germany 

3

A-83-01 Usage And Synthesis

Description

A 83-01 (909910-43-6) is a potent and selective ALK4, 5 and 7 inhibitor.1,2?IC50 = 45, 12 and 7.5 nM respectively. Prevents phosphorylation of Smad2/3 and growth inhibition induced by TGFβ.2?Inhibits differentiation of rat induced pluripotent stem cells and increases clonal expansion efficiency.3?Together with AMI-5, A83-01 enabled Oct4-induced reprogramming of mouse embryonic fibroblasts.4?Cell permeable. Active in vivo.

Uses

A 83-01 is a selective inhibitor of TGF-β type I receptor. A 83-01 treatment increases tumor permeability.

Uses

A 83-01 has been used as an inhibitor of transforming growth factor β kinase type 1 receptor.

Biological Activity

Selective inhibitor of TGF- β type I receptor ALK5 kinase, type I activin/nodal receptor ALK4 and type I nodal receptor ALK7 (IC 50 values are 12, 45 and 7.5 nM respectively). Blocks phosphorylation of Smad2 and inhibits TGF- β -induced epithelial-to-mesenchymal transition. Only weakly inhibits ALK-1, -2, -3, -6 and MAPK activity. More potent than SB 431542 (4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol -2-yl]benzamide). Inhibits differentiation of rat induced pluripotent stem cells (riPSCs) and increases clonal expansion efficiency. Helps maintain homogeneity and long-term in vitro self-renewal of human iPSCs.

Biochem/physiol Actions

A 83-01 is a TGFβ kinase/activin receptor-like kinase (ALK 5) inhibitor (IC50=12 nM) that prevents phosphorylation of Smad2/3 and inhibits growth induced by TGFβ. A 83-01 blocks phosphorylation of Smad2 and inhibits TGF-β-induced epithelial-to-mesenchymal transition. Also, A 83-01 inhibits the transcriptional activity induced by TGFβ type I receptor ALK-5, activin type IB receptor ALK-4 and nodal type I receptor ALK-7. A-83-01 induces an expansion of neonatal Nkx2.5-eGFP (+) cells.

Enzyme inhibitor

This TGFb inhibitor (FW = 421.52 g/mol; CAS 909910-43-6; Solubility: 50 mM in DMSO), named 3-(6-methyl-2-pyridinyl)-N-phenyl-4-(4-quinolinyl)-1H-pyrazole-1-carbothioamide, selectively targets TGF-β type I receptor ALK5 kinase (IC50 = 12 nM), Type I Activin/Nodal receptor ALK4 (IC50 = 45 nM), and type I nodal receptor ALK7 (IC50 = 7.5 nM), blocking the phosphorylation of Smad2 and inhibiting TGF-β-induced epithelial-to-mesenchymal transitions. TGF-β signaling inhibitors represent a useful strategy for treating patients with tumor growth and metastasis in advanced cancer. A-83-01 only weakly inhibits ALK-1, ALK-2, ALK-3, ALK-6 and MAPK. It also has little or no effect on bone morphogenetic protein type I receptors, p38 mitogen-activated protein kinase, or extracellular regulated kinase. A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-β. Its use also instrumental in demonstrating that attachment to Laminin-111 facilitates TGF-β-induced expression of matrix metalloproteinase-2 in synovial fibroblasts.

storage

-20°C (protect from light)

References

1) Vogt. et al. (2011), The specificities of small molecule inhibitors of the TGFβ and BMP pathways; Cell Signal., 23 1831 2) Tojo et al. (2012), Characteristic differences among osteogenic cell populations of rat bone marrow stromal cells isolated from untreated, hemolyzed or Ficoll-treated marrow; Cancer Sci., 96 791 3) Li et al. (2009), Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors; Cell Stem Cell, 4 16 4) Yuan et al. (2011), Brief report: combined chemical treatment enables Oct4-induced reprogramming from mouse embryonic fibroblasts; Stem Cells, 29 549

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