The specificities of small molecule inhibitors of the TGFβ and BMP pathways
The specificities of small molecule inhibitors of the TGFβ and BMP pathways
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DOI：
10.1016/j.cellsig.2011.06.019
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发表时间：
2011-11-01
影响因子：
4.8
通讯作者：
Sapkota, Gopal P.
中科院分区：
文献类型：
--
作者：
Vogt, Janis;Traynor, Ryan;Sapkota, Gopal P.
作为转化生长因子β信号和骨形态发生蛋白信号的介体，1型受体丝氨酸苏氨酸激酶的小分子抑制物(ALKs1-7)在细胞和生物体中被广泛用于评估它们的生理作用。虽然所有这些抑制剂都被报道为特定ALK的“选择性”抑制剂，但针对广泛的蛋白激酶还没有进行广泛的特异性测试。在这项研究中，我们研究了转化生长因子β途径最常用的小分子抑制剂(SB-431542、SB-505124、LY-364947和A-83-01)和骨形态发生蛋白途径(多索吗啡和低密度脂蛋白-193189)针对一组覆盖人类基因组广谱的多达123个蛋白激酶的特异性和效力。我们证明，转化生长因子β途径的抑制剂比骨形态发生蛋白途径的抑制剂具有相对更高的选择性。根据我们的特异性和有效性以及已发表的数据，我们推荐SB-505124作为ALKS4、5和7以及转化生长因子β途径的抑制剂最合适的分子。我们不建议使用多索吗啡，也称为化合物C，作为BMP途径的抑制剂。虽然LDN-193189是一种多索吗啡衍生物，是一种非常有效的ALK2/3和骨形态发生蛋白途径的抑制剂，但我们发现，在足以抑制ALK2/3的浓度下，它可以有效地抑制其他一些蛋白激酶，因此必须谨慎使用它作为一种选择性的骨形态发生蛋白途径抑制剂。我们的观察强调了在使用这些小分子抑制剂来评估BMP和转化生长因子β途径的生理作用时需要谨慎的必要性。(C)2011 Elsevier Inc.保留所有权利。
Small molecule inhibitors of type 1 receptor serine threonine kinases (ALKs1-7), the mediators of TGF beta and BMP signals, have been employed extensively to assess their physiological roles in cells and organisms. While all of these inhibitors have been reported as "selective" inhibitors of specific ALKs, extensive specificity tests against a wide array of protein kinases have not been performed. In this study, we examine the specificities and potencies of the most frequently used small molecule inhibitors of the TGF beta pathway (SB-431542, SB-505124, LY-364947 and A-83-01) and the BMP pathway (Dorsomorphin and LDN-193189) against a panel of up to 123 protein kinases covering a broad spectrum of the human kinome. We demonstrate that the inhibitors of the TGF beta pathway are relatively more selective than the inhibitors of the BMP pathway. Based on our specificity and potency profile and published data, we recommend SB-505124 as the most suitable molecule for use as an inhibitor of ALKs 4,5 and 7 and the TGF beta pathway. We do not recommend Dorsomorphin, also called Compound C, for use as an inhibitor of the BMP pathway. Although LDN-193189, a Dorsomorphin derivative, is a very potent inhibitor of ALK2/3 and the BMP-pathway, we found that it potently inhibited a number of other protein kinases at concentrations sufficient to inhibit ALK2/3 and its use as a selective BMP-pathway inhibitor has to be considered cautiously. Our observations have highlighted the need for caution when using these small molecule inhibitors to assess the physiological roles of BMP and TGF beta pathways. (C) 2011 Elsevier Inc. All rights reserved.