2. Academic Validation
  3. Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors

Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors

  • Bioorg Med Chem. 2017 Feb 15;25(4):1320-1328. doi: 10.1016/j.bmc.2016.11.034.
Li Tan 1,  Deepak Gurbani 2,  Ellen L Weisberg 3,  Douglas S Jones 4,  Suman Rao 5,  William D Singer 6,  Faviola M Bernard 6,  Samar Mowafy 7,  Annie Jenney 8,  Guangyan Du 1,  Atsushi Nonami 3,  James D Griffin 3,  Douglas A Lauffenburger 9,  Kenneth D Westover 10,  Peter K Sorger 11,  Nathanael S Gray 12
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Biochemistry, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
  • 3 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
  • 4 HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 5 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; HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 6 Department of Biochemistry, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Department of Radiation Oncology, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
  • 7 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; Misr International University, Km 28 Cairo, Ismailia Rd., Ahmed Orabi Dist., Cairo, Egypt.
  • 8 HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 9 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • 10 Department of Biochemistry, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Department of Radiation Oncology, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA. Electronic address: Kenneth.Westover@UTSouthwestern.edu.
  • 11 HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: Peter_Sorger@hms.harvard.edu.
  • 12 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. Electronic address: Nathanael_Gray@dfci.harvard.edu.
PMID: 28038940 DOI: 10.1016/j.bmc.2016.11.034
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.

Keywords

Cancer; Cytokine secretion; Multitarget; Polypharmacology; TAK1.

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