2. Academic Validation
  3. Structure-guided development of covalent TAK1 inhibitors

Structure-guided development of covalent TAK1 inhibitors

  • Bioorg Med Chem. 2017 Feb 1;25(3):838-846. doi: 10.1016/j.bmc.2016.11.035.
Li Tan 1,  Deepak Gurbani 2,  Ellen L Weisberg 3,  John C Hunter 2,  Lianbo Li 2,  Douglas S Jones 4,  Scott B Ficarro 1,  Samar Mowafy 5,  Chun-Pong Tam 1,  Suman Rao 6,  Guangyan Du 1,  James D Griffin 3,  Peter K Sorger 7,  Jarrod A Marto 1,  Kenneth D Westover 8,  Nathanael S Gray 9
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; Department of Radiation Oncology, 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; Misr International University, Km 28 Cairo, Ismailia Rd., Ahmed Orabi Dist., Cairo, Egypt.
  • 6 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.
  • 7 HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 8 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.
  • 9 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: 28011204 DOI: 10.1016/j.bmc.2016.11.035
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.

Keywords

2,4-Disubstituted pyrimidine; Covalent inhibitors; Structure-activity relationship; Structure-based design; TAK1 kinase inhibitors.

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