Structure-guided development of covalent TAK1 inhibitors

Li Tan, Deepak Gurbani, Ellen L. Weisberg, John C. Hunter, Lianbo Li, Douglas S. Jones, Scott B. Ficarro, Samar Mowafy, Chun Pong Tam, Suman Rao, Guangyan Du, James D. Griffin, Peter K. Sorger, Jarrod A. Marto, Kenneth D. Westover, Nathanael S. Gray

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)838-846
Number of pages9
JournalBioorganic and Medicinal Chemistry
Issue number3
StatePublished - 2017


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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


Dive into the research topics of 'Structure-guided development of covalent TAK1 inhibitors'. Together they form a unique fingerprint.

Cite this