title: Structure-guided development of covalent TAK1 inhibitors.
abstract: TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the 'DFG-motif' of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.
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; Department of Radiation Oncology, 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: 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: John C
authors.initials: JC
authors.lastname: Hunter
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: Lianbo
authors.initials: L
authors.lastname: Li
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.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Ficarro
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: 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: Chun-Pong
authors.initials: CP
authors.lastname: Tam
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 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: James D
authors.initials: JD
authors.lastname: Griffin
authors.affiliation: HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
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.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Marto
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: 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: D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000099151:MAP Kinase Kinase Kinase 7; C030986:pyrimidine
keywords: 2,4-Disubstituted pyrimidine; Covalent inhibitors; Structure-activity relationship; Structure-based design; TAK1 kinase inhibitors