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.

InChI

InChI=1S/C25H19N5S/c1-17-8-7-13-23(27-17)24-21(19-14-15-26-22-12-6-5-11-20(19)22)16-30(29-24)25(31)28-18-9-3-2-4-10-18/h2-16H,1H3,(H,28,31)

InChIKey

HIJMSZGHKQPPJS-UHFFFAOYSA-N

SMILES

N1(C(NC2=CC=CC=C2)=S)C=C(C2C3C(N=CC=2)=CC=CC=3)C(C2=NC(C)=CC=C2)=N1

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] JANIS VOGT  Gopal P S  Ryan Traynor. The specificities of small molecule inhibitors of the TGFß and BMP pathways[J]. Cellular signalling, 2011, 23 11: Pages 1831-1842. DOI:10.1016/j.cellsig.2011.06.019
[2] HIDEKI AGATA . Characteristic differences among osteogenic cell populations of rat bone marrow stromal cells isolated from untreated, hemolyzed or Ficoll-treated marrow[J]. Cytotherapy, 2012, 14 7: Pages 791-801. DOI:10.3109/14653249.2012.674639
[3] WENLIN LI. Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors.[J]. Cell stem cell, 2009, 4 1: 16-19. DOI:10.1016/j.stem.2008.11.014
[4] XU YUAN. Brief Report: Combined Chemical Treatment Enables Oct4-Induced Reprogramming from Mouse Embryonic Fibroblasts†‡§[J]. STEM CELLS, 2011, 29 3: 549-553. DOI:10.1002/stem.594

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