title: Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling.
abstract: Transforming growth factor (TGFbeta) is a 25-kDa dimeric polypeptide that plays a key role in a variety of physiological processes and disease states. Blocking TGFbeta signaling represents a potentially powerful and conceptually novel approach to the treatment of disorders in which the signaling pathway is constitutively activated, such as cancer, chronic inflammation with fibrosis and select immune disorders. In this paper, we describe the biological properties of a novel series of quinazoline-derived inhibitors of the type I transforming growth factor receptor kinase (TbetaKIs) that bind to the ATP-binding site and keep the kinase in its inactive conformation. These compounds effectively inhibited TGFbeta-induced Smad2 phosphorylation in cultured cells in vitro with an IC(50) between 20 and 300 nM. Moreover, TbetaKIs were able to broadly block TGFbeta-induced reporter gene activation. Finally, TbetaKIs inhibited TGFbeta-mediated growth inhibition of normal murine mammary epithelial cells (NMuMG) and mink lung epithelial cells (Mv1Lu), and TGFbeta-induced epithelial-mesenchymal transdifferentiation (EMT) of NMuMG cells. Thus, these chemical TbetaKIs have the potential to be further developed as anti-cancer and -fibrosis agents. In addition, they represent valuable new tools for dissecting the biochemical mechanisms of TGFbeta signal transduction and understanding the role of TGFbeta signaling pathways in different physiological and disease processes.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, UMDNJ-Robert Wood Johnson Medical School and The Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Ge
authors.forename: Vaishali
authors.initials: V
authors.lastname: Rajeev
authors.forename: Gayathri
authors.initials: G
authors.lastname: Subramanian
authors.forename: Kim A
authors.initials: KA
authors.lastname: Reiss
authors.forename: David
authors.initials: D
authors.lastname: Liu
authors.forename: Linda
authors.initials: L
authors.lastname: Higgins
authors.forename: Alison
authors.initials: A
authors.lastname: Joly
authors.forename: Sundeep
authors.initials: S
authors.lastname: Dugar
authors.forename: Jit
authors.initials: J
authors.lastname: Chakravarty
authors.forename: Margaret
authors.initials: M
authors.lastname: Henson
authors.forename: Glenn
authors.initials: G
authors.lastname: McEnroe
authors.forename: George
authors.initials: G
authors.lastname: Schreiner
authors.forename: Michael
authors.initials: M
authors.lastname: Reiss
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004347:Drug Interactions; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051899:Smad2 Protein; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D010455:Peptides; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta