SB-505124 is a selective inhibitor of transforming growth factor-β type I receptors ALK4, ALK5, and ALK7
SB-505124 is a selective inhibitor of transforming growth factor-β type I receptors ALK4, ALK5, and ALK7
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DOI：
10.1124/mol.65.3.744
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发表时间：
2004-03-01
影响因子：
3.6
通讯作者：
Roberts, AB
中科院分区：
文献类型：
--
作者：
Byfield, SD;Major, C;Roberts, AB
临床上，非常需要能够控制转化生长因子（TGF-β）的致病作用和/或调节TGF-β在正常应答中的作用的小分子抑制剂。预计TGF-β信号传导的抑制将增强皮肤伤口的再上皮化并减少瘢痕纤维化。为治疗开发的TGF-β信号通路的选择性小分子抑制剂也将是实验性剖析这种复杂通路的有力工具，特别是其与其他信号通路的串扰。在这项研究中，我们表征了2-（5-苯并[1，3]间二氧杂环戊烯-5-基-2-叔丁基-3H-咪唑-4-基）-6-甲基吡啶盐酸盐（SB-505124），这是一类与p38咪唑抑制剂相关的新型小分子抑制剂，可抑制TGF-β I型受体丝氨酸/苏氨酸激酶（称为激活素受体样激酶（ALK）5）。我们证明，这种化合物选择性和浓度依赖性抑制ALK 4-，ALK 5-和ALK 7-依赖性激活下游细胞质信号转导，Smad 2和Smad 3，和TGF-β诱导的促分裂原活化蛋白激酶途径成分，但不改变ALK 1，ALK 2，ALK 3或ALK 6诱导的Smad信号。SB-505124还阻断TGF-β作用的更复杂的终点，如其消除TGF-β 1治疗引起的细胞死亡的能力所证明的。SB-505124的效力是先前描述的相关ALK 5抑制剂SB-431542的三到五倍。
Clinically, there is a great need for small molecule inhibitors that could control pathogenic effects of transforming growth factor (TGF-beta) and/or modulate effects of TGF-beta in normal responses. Inhibition of TGF-beta signaling would be predicted to enhance re-epithelialization of cutaneous wounds and reduce scarring fibrosis. Selective small molecule inhibitors of the TGF-beta signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized 2-(5-benzo[1,3]dioxol-5-yl-2-tert-butyl-3H-imidazol-4-yl)-6-methylpyridine hydrochloride (SB-505124), a member of a new class of small molecule inhibitors related to imidazole inhibitors of p38, which inhibit the TGF-beta type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. We demonstrate that this compound selectively and concentration-dependently inhibits ALK4-, ALK5-, and ALK 7-dependent activation of downstream cytoplasmic signal transducers, Smad2 and Smad3, and of TGF-beta-induced mitogen-activated protein kinase pathway components but does not alter ALK1, ALK2, ALK3 or ALK6-induced Smad signaling. SB-505124 also blocks more complex endpoints of TGF-beta action, as evidenced by its ability to abrogate cell death caused by TGF-beta1 treatment. SB-505124 is three to five times more potent than a related ALK5 inhibitor described previously, SB-431542.