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A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase.

Publication ,  Journal Article
Scarneo, SA; Hughes, PF; Yang, KW; Carlson, DA; Gurbani, D; Westover, KD; Haystead, TAJ
Published in: J Biol Chem
February 7, 2020

Interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-4, as well as transforming growth factor β-activated kinase 1 (TAK1), are protein kinases essential for transducing inflammatory signals from interleukin receptors. IRAK family proteins and TAK1 have high sequence identity within the ATP-binding pocket, limiting the development of highly selective IRAK-1/4 or TAK1 inhibitors. Beyond kinase activity, IRAKs and TAK1 act as molecular scaffolds along with other signaling proteins, complicating the interpretation of experiments involving knockin or knockout approaches. In contrast, pharmacological manipulation offers the promise of targeting catalysis-mediated signaling without grossly disrupting the cellular architecture. Recently, we reported the discovery of takinib, a potent and highly selective TAK1 inhibitor that has only marginal activity against IRAK-4. On the basis of the TAK1-takinib complex structure and the structure of IRAK-1/4, here we defined critical contact sites of the takinib scaffold within the nucleotide-binding sites of each respective kinase. Kinase activity testing of takinib analogs against IRAK-4 identified a highly potent IRAK-4 inhibitor (HS-243). In a kinome-wide screen of 468 protein kinases, HS-243 had exquisite selectivity toward both IRAK-1 (IC50 = 24 nm) and IRAK-4 (IC50 = 20 nm), with only minimal TAK1-inhibiting activity (IC50 = 0.5 μm). Using HS-243 and takinib, we evaluated the consequences of cytokine/chemokine responses after selective inhibition of IRAK-1/4 or TAK1 in response to lipopolysaccharide challenge in human rheumatoid arthritis fibroblast-like synoviocytes. Our results indicate that HS-243 specifically inhibits intracellular IRAKs without TAK1 inhibition and that these kinases have distinct, nonredundant signaling roles.

Duke Scholars

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 7, 2020

Volume

295

Issue

6

Start / End Page

1565 / 1574

Location

United States

Related Subject Headings

  • THP-1 Cells
  • Synoviocytes
  • Signal Transduction
  • Protein Kinase Inhibitors
  • Models, Molecular
  • MAP Kinase Kinase Kinases
  • Lipopolysaccharides
  • Interleukin-1 Receptor-Associated Kinases
  • Humans
  • Biochemistry & Molecular Biology
 

Citation

APA
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ICMJE
MLA
NLM
Scarneo, S. A., Hughes, P. F., Yang, K. W., Carlson, D. A., Gurbani, D., Westover, K. D., & Haystead, T. A. J. (2020). A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase. J Biol Chem, 295(6), 1565–1574. https://doi.org/10.1074/jbc.RA119.011857
Scarneo, Scott A., Philip F. Hughes, Kelly W. Yang, David A. Carlson, Deepak Gurbani, Kenneth D. Westover, and Timothy A. J. Haystead. “A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase.J Biol Chem 295, no. 6 (February 7, 2020): 1565–74. https://doi.org/10.1074/jbc.RA119.011857.
Scarneo SA, Hughes PF, Yang KW, Carlson DA, Gurbani D, Westover KD, et al. A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase. J Biol Chem. 2020 Feb 7;295(6):1565–74.
Scarneo, Scott A., et al. “A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase.J Biol Chem, vol. 295, no. 6, Feb. 2020, pp. 1565–74. Pubmed, doi:10.1074/jbc.RA119.011857.
Scarneo SA, Hughes PF, Yang KW, Carlson DA, Gurbani D, Westover KD, Haystead TAJ. A highly selective inhibitor of interleukin-1 receptor-associated kinases 1/4 (IRAK-1/4) delineates the distinct signaling roles of IRAK-1/4 and the TAK1 kinase. J Biol Chem. 2020 Feb 7;295(6):1565–1574.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

February 7, 2020

Volume

295

Issue

6

Start / End Page

1565 / 1574

Location

United States

Related Subject Headings

  • THP-1 Cells
  • Synoviocytes
  • Signal Transduction
  • Protein Kinase Inhibitors
  • Models, Molecular
  • MAP Kinase Kinase Kinases
  • Lipopolysaccharides
  • Interleukin-1 Receptor-Associated Kinases
  • Humans
  • Biochemistry & Molecular Biology