Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors

Li Tan, Suman Rao, Samar Mowafy, Guangyan Du, Nathanael S. Gray, Deepak Gurbani, Ellen L. Weisberg, Douglas S. Jones, William D. Singer, Faviola M. Bernard, Annie Jenney, Atsushi Nonami, James D. Griffin, Douglas A. Lauffenburger, Kenneth D. Westover, Peter K. Sorger

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1320-1328
Number of pages9
JournalBioorganic and Medicinal Chemistry
Issue number4
Publication statusPublished - 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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