Ge Rongrong, Rajeev Vaishali, Subramanian Gayathri, Reiss Kim A, Liu David, Higgins Linda, Joly Alison, Dugar Sundeep, Chakravarty Jit, Henson Margaret, McEnroe Glenn, Schreiner George, Reiss Michael
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.
Biochem Pharmacol. 2004 Jul 1;68(1):41-50. doi: 10.1016/j.bcp.2004.03.011.
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.
转化生长因子（TGFβ）是一种25 kDa的二聚体多肽，在多种生理过程和疾病状态中起关键作用。阻断TGFβ信号传导是一种潜在的强大且概念新颖的治疗方法，可用于治疗信号通路持续激活的疾病，如癌症、伴有纤维化的慢性炎症以及某些免疫疾病。在本文中，我们描述了一系列新型喹唑啉衍生的I型转化生长因子受体激酶抑制剂（TβKIs）的生物学特性，这些抑制剂与ATP结合位点结合并使激酶保持无活性构象。这些化合物在体外培养细胞中有效抑制TGFβ诱导的Smad2磷酸化，IC50在20至300 nM之间。此外，TβKIs能够广泛阻断TGFβ诱导的报告基因激活。最后，TβKIs抑制TGFβ介导的正常小鼠乳腺上皮细胞（NMuMG）和水貂肺上皮细胞（Mv1Lu）的生长抑制，以及TGFβ诱导的NMuMG细胞上皮 - 间质转分化（EMT）。因此，这些化学TβKIs有潜力进一步开发为抗癌和抗纤维化药物。此外，它们是剖析TGFβ信号转导生化机制以及理解TGFβ信号通路在不同生理和疾病过程中作用的有价值的新工具。
