| Literature DB >> 28038940 |
Li Tan1, Deepak Gurbani2, Ellen L Weisberg3, Douglas S Jones4, Suman Rao5, William D Singer6, Faviola M Bernard6, Samar Mowafy7, Annie Jenney8, Guangyan Du1, Atsushi Nonami3, James D Griffin3, Douglas A Lauffenburger9, Kenneth D Westover10, Peter K Sorger11, Nathanael S Gray12.
Abstract
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.Entities:
Keywords: Cancer; Cytokine secretion; Multitarget; Polypharmacology; TAK1
Mesh：
Substances：
Year: 2016 PMID： 28038940 PMCID： PMC5484535 DOI： 10.1016/j.bmc.2016.11.034
Source DB: PubMed Journal: Bioorg Med Chem ISSN： 0968-0896 Impact factor: 3.641