Structural Genomics Consortium, Institute for Pharmaceutical Chemistry and Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.
ACS Chem Biol. 2020 Apr 17;15(4):862-870. doi: 10.1021/acschembio.0c00076. Epub 2020 Mar 20.
The transforming growth factor beta-receptor I/activin receptor-like kinase 5 (TGFBR1/ALK5) and its close homologue ALK4 are receptor protein kinases associated with the development of diverse diseases, including cancer, fibrosis, heart diseases, and dysfunctional immune response. Therefore, ALK4/5 are among the most studied kinases, and several inhibitors have been developed. However, current commercially available inhibitors either lack selectivity or have not been comprehensively characterized, limiting their value for studying ALK4/5 function in cellular systems. To this end, we report the characterization of the 2-oxo-imidazopyridine, TP-008, a potent chemical probe with dual activity for ALK4 and ALK5 as well as the development of a matching negative control compound. TP-008 has excellent cellular potency and strongly abrogates phosphorylation of the substrate SMAD2 (mothers against decapentaplegic homologue 2). Thus, this chemical probe offers an excellent tool for mechanistic studies on the ALK4/5 signaling pathway and the contribution of these targets to disease.
转化生长因子β受体 I/激活素受体样激酶 5（TGFBR1/ALK5）及其密切同源物 ALK4 是与多种疾病（包括癌症、纤维化、心脏病和功能失调的免疫反应）的发生相关的受体蛋白激酶。因此，ALK4/5 是研究最多的激酶之一，已经开发出几种抑制剂。然而，目前市售的抑制剂要么缺乏选择性，要么没有得到全面表征，限制了它们在细胞系统中研究 ALK4/5 功能的价值。为此，我们报告了 2-氧代-咪唑并吡啶 TP-008 的特征，它是一种针对 ALK4 和 ALK5 具有双重活性的有效化学探针，以及与其匹配的负对照化合物的开发。TP-008 具有优异的细胞效力，并强烈阻断底物 SMAD2（母亲抗颅面发育不全同源物 2）的磷酸化。因此，这种化学探针为 ALK4/5 信号通路的机制研究以及这些靶点对疾病的贡献提供了一个极好的工具。
