Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent

2008 ◽  
Vol 51 (7) ◽  
pp. 2302-2306 ◽  
Author(s):  
Hong-yu Li ◽  
William T. McMillen ◽  
Charles R. Heap ◽  
Denis J. McCann ◽  
Lei Yan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Antitumor Agent ◽  
Transforming Growth Factor Β ◽  
Kinase Domain ◽  
Receptor Type ◽  
Type I ◽  
Receptor Kinase ◽  
Orally Bioavailable ◽  
Β Receptor

scholarly journals Transforming Growth Factor-β Receptor Type I-dependent Fibrogenic Gene Program Is Mediated via Activation of Smad1 and ERK1/2 Pathways

2007 ◽  
Vol 282 (14) ◽  
pp. 10405-10413 ◽  
Author(s):  
Jaspreet Pannu ◽  
Sashidhar Nakerakanti ◽  
Edwin Smith ◽  
Peter ten Dijke ◽  
Maria Trojanowska
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Type ◽  
Type I ◽  
Β Receptor

scholarly journals Repression of transforming growth factor-β receptor type I promoter expression by Sp1 deficiency

Oncogene ◽  
2000 ◽  
Vol 19 (40) ◽  
pp. 4660-4667 ◽  
Author(s):  
Sumudra Periyasamy ◽  
Sudhakar Ammanamanchi ◽  
Manoranjani PM Tillekeratne ◽  
Michael G Brattain
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Receptor Type ◽  
Type I ◽  
Β Receptor

scholarly journals Transforming Growth Factor β Receptor Signaling and Endocytosis Are Linked through a COOH Terminal Activation Motif in the Type I Receptor

2001 ◽  
Vol 12 (9) ◽  
pp. 2881-2893 ◽  
Author(s):  
Nandor Garamszegi ◽  
Jules J. E. Doré ◽  
Sumedha G. Penheiter ◽  
Maryanne Edens ◽  
Diying Yao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Kinase Domain ◽  
Type I ◽  
Receptor Signaling ◽  
Down Regulation ◽  
Critical Function ◽  
Β Receptor

Transforming growth factor β (TGF-β) coordinates a number of biological events important in normal and pathophysiological growth. In this study, deletion and substitution mutations were used to identify receptor motifs modulating TGF-β receptor activity. Initial experiments indicated that a COOH-terminal sequence between amino acids 482–491 in the kinase domain of the type I receptor was required for ligand-induced receptor signaling and down-regulation. These 10 amino acids are highly conserved in mammalian, Xenopus, andDrosophila type I receptors. Although mutation or deletion of the region (referred to as the NANDOR BOX, for nonactivating non–down-regulating) abolishes TGF-β–dependent mitogenesis, transcriptional activity, type I receptor phosphorylation, and down-regulation in mesenchymal cultures, adjacent mutations also within the kinase domain are without effect. Moreover, a kinase-defective type I receptor can functionally complement a mutant BOX expressing type I receptor, documenting that when the BOX mutant is activated, it has kinase activity. These results indicate that the sequence between 482 and 491 in the type I receptor provides a critical function regulating activation of the TGF-β receptor complex.

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
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