title: Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors.
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.
authors.affiliation: 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.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Biochemistry, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Gurbani
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Weisberg
authors.affiliation: 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.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Suman
authors.initials: S
authors.lastname: Rao
authors.affiliation: 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.
authors.forename: William D
authors.initials: WD
authors.lastname: Singer
authors.affiliation: 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.
authors.forename: Faviola M
authors.initials: FM
authors.lastname: Bernard
authors.affiliation: 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.
authors.forename: Samar
authors.initials: S
authors.lastname: Mowafy
authors.affiliation: HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Jenney
authors.affiliation: 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.
authors.forename: Guangyan
authors.initials: G
authors.lastname: Du
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nonami
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: 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.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Westover
authors.affiliation: HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA. Electronic address: Peter_Sorger@hms.harvard.edu.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Sorger
authors.affiliation: 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.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D016207:Cytokines; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D000099151:MAP Kinase Kinase Kinase 7
keywords: Cancer; Cytokine secretion; Multitarget; Polypharmacology; TAK1