使用新型共价TAK1抑制剂对以TAK1为中心的多药理学研究。
Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
作者信息
Tan Li, Gurbani Deepak, Weisberg Ellen L, Jones Douglas S, Rao Suman, Singer William D, Bernard Faviola M, Mowafy Samar, Jenney Annie, Du Guangyan, Nonami Atsushi, Griffin James D, Lauffenburger Douglas A, Westover Kenneth D, Sorger Peter K, Gray Nathanael S
机构信息
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
Department of Biochemistry, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
出版信息
Bioorg Med Chem. 2017 Feb 15;25(4):1320-1328. doi: 10.1016/j.bmc.2016.11.034. Epub 2016 Dec 7.
Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.
靶向多药理学提供了一种治疗诸如癌症等具有复杂多基因病因疾病的有效方法，前提是能够发现具有有利活性谱的化合物。新型共价TAK1抑制剂在细胞环境中因其抑制TAK1激酶的能力及其多药理学特性而得到验证。几种抑制剂模拟了已报道的TAK1抑制剂5Z-7-氧代扎烯醇，具有相当的疗效和互补的激酶选择性谱。化合物5在来自各种癌症类型的RAS突变和野生型RAS细胞系中表现出最大的效力。5的生物素化衍生物27用于验证细胞中TAK1的结合。新描述的抑制剂为进一步开发以TAK1为中心的多靶点癌症及其他疾病抑制剂提供了有用的工具。
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