Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors:  A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7

2006 ◽  
Vol 49 (6) ◽  
pp. 2138-2142 ◽  
Author(s):  
Hong-yu Li ◽  
Yan Wang ◽  
Charles R. Heap ◽  
Chi-Hsin R. King ◽  
Sreenivasa R. Mundla ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Kinase Domain ◽  
Type I ◽  
Type Ii ◽  
Receptor Kinase ◽  
Mixed Lineage Kinase

Synthesis and Activity of New Aryl- and Heteroaryl-Substituted Pyrazole Inhibitors of the Transforming Growth Factor-β Type I Receptor Kinase Domain

2003 ◽  
Vol 46 (19) ◽  
pp. 3953-3956 ◽  
Author(s):  
J. Scott Sawyer ◽  
Bryan D. Anderson ◽  
Douglas W. Beight ◽  
Robert M. Campbell ◽  
Michael L. Jones ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Kinase Domain ◽  
Type I ◽  
Receptor Kinase

scholarly journals Integrin β1Signaling Is Necessary for Transforming Growth Factor-β Activation of p38MAPK and Epithelial Plasticity

2001 ◽  
Vol 276 (50) ◽  
pp. 46707-46713 ◽  
Author(s):  
Neil A. Bhowmick ◽  
Roy Zent ◽  
Mayshan Ghiassi ◽  
Maureen McDonnell ◽  
Harold L. Moses
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dominant Negative ◽  
Receptor Expression ◽  
Type I ◽  
Type Ii

Transforming growth factor-β (TGF-β) can induce epithelial to mesenchymal transdifferentiation (EMT) in mammary epithelial cells. TGF-β-meditated EMT involves the stimulation of a number of signaling pathways by the sequential binding of the type II and type I serine/threonine kinase receptors, respectively. Integrins comprise a family of heterodimeric extracellular matrix receptors that mediate cell adhesion and intracellular signaling, hence making them crucial for EMT progression. In light of substantial evidence indicating TGF-β regulation of various β1integrins and their extracellular matrix ligands, we examined the cross-talk between the TGF-β and integrin signal transduction pathways. Using an inducible system for the expression of a cytoplasmically truncated dominant negative TGF-β type II receptor, we blocked TGF-β-mediated growth inhibition, transcriptional activation, and EMT progression. Dominant negative TGF-β type II receptor expression inhibited TGF-β signaling to the SMAD and AKT pathways, but did not block TGF-β-mediated p38MAPK activation. Interestingly, blocking integrin β1function inhibited TGF-β-mediated p38MAPK activation and EMT progression. Limiting p38MAPK activity through the expression of a dominant negative-p38MAPK also blocked TGF-β-mediated EMT. In summary, TGF-β-mediated p38MAPK activation is dependent on functional integrin β1, and p38MAPK activity is required but is not sufficient to induce EMT.

scholarly journals Inhibition of Pulmonary and Skeletal Metastasis by a Transforming Growth Factor-β Type I Receptor Kinase Inhibitor

2006 ◽  
Vol 66 (13) ◽  
pp. 6714-6721 ◽  
Author(s):  
Abhik Bandyopadhyay ◽  
Joseph K. Agyin ◽  
Long Wang ◽  
Yuping Tang ◽  
Xiufen Lei ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Skeletal Metastasis ◽  
Transforming Growth Factor Β ◽  
Type I ◽  
Receptor Kinase
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