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

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9 引用 (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.

ジャーナルBioorganic and Medicinal Chemistry
出版物ステータス出版済み - 2017

All Science Journal Classification (ASJC) codes

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

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    Tan, L., Rao, S., Mowafy, S., Du, G., Gray, N. S., Gurbani, D., Weisberg, E. L., Jones, D. S., Singer, W. D., Bernard, F. M., Jenney, A., Nonami, A., Griffin, J. D., Lauffenburger, D. A., Westover, K. D., & Sorger, P. K. (2017). Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. Bioorganic and Medicinal Chemistry, 25(4), 1320-1328.