Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors

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

doi:10.1016/j.bmc.2016.11.034

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. Epub 2016 Dec 7.

Authors

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

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.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cytokines / metabolism
Dose-Response Relationship, Drug
Humans
MAP Kinase Kinase Kinases / antagonists & inhibitors*
MAP Kinase Kinase Kinases / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Cytokines
Protein Kinase Inhibitors
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7

Abstract

Publication types

MeSH terms

Substances

Grants and funding