Small molecule antagonists binding of the TGF-β1/TGF-β receptor interaction
Small molecule antagonists binding of the TGF-β1/TGF-β receptor interaction
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DOI：
10.1385/mo:23:4:553
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发表时间：
2006-01-01
期刊：
影响因子：
3.4
通讯作者：
Dart, Richard A.
中科院分区：
文献类型：
--
作者：
Burmester, James K.;Salzman, Sherry A.;Dart, Richard A.
转化生长因子（TGF）-β的过度和不适当的作用已经涉及几种疾病过程的发病机制，特别是癌症和纤维化。为了鉴定可能具有治疗潜力的TGF-配体结合域的拮抗剂，我们筛选了国家癌症研究所开放获取化学库中抑制TGF-β与II型受体（T β RII）结合的分子。筛选了约30，000个分子，鉴定出5种结构相关的分子，它们降低TGF-β 1与可溶性T β RII的结合，ED 50约为10 μ M。化学物质阻断TGF-β对Mv 1 Lu细胞生长的抑制、TGF-β诱导的由TGF-β反应元件驱动的荧光素酶表达以及通过北方印迹检测的纤溶酶原抑制剂mRNA的诱导。相比之下，这些化学物质并不阻断激活素诱导的细胞生长抑制。我们的研究结果确定了一种新的化学基团，可以阻断TGF-β与其受体的结合，并可能导致新的疾病治疗方法。
Excessive and inappropriate action of transforming growth factor (TGF)-beta has been implicated in the pathogenesis of several disease processes, especially cancer and fibrosis. To identify antagonists of the TGF-ligand-binding domain that may have therapeutic potential, we screened the National Cancer Institute open access chemical repository for molecules that inhibited binding of TGF-beta to the type II receptor (T beta RII). About 30,000 molecules were screened resulting in the identification of five structurally related molecules that reduced binding of TGF-beta 1 to soluble T beta RII with an ED50 of approx 10 mu M. The chemicals blocked inhibition of Mv1Lu cell growth by TGF-beta, TGF-beta-induced expression of luciferase driven by the TGF-beta response element, and induction of plasminogen inhibitor mRNA detected by Northern blot. In contrast, the chemicals did not block activin-induced inhibition of cell growth. Our results identify a novel chemical group that blocks binding of TGF-beta to its receptor and may result in novel treatment for disease.