A Small-Molecule Inhibitor to the Cytokine Interleukin-4.

Autor:	Quinnell SP; Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States., Leifer BS; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States., Nestor ST; Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States., Tan K; Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States., Sheehy DF; Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States., Ceo L; Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States., Doyle SK; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States., Koehler AN; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States., Vegas AJ; Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical biology [ACS Chem Biol] 2020 Oct 16; Vol. 15 (10), pp. 2649-2654. Date of Electronic Publication: 2020 Sep 16.
DOI:	10.1021/acschembio.0c00615
Abstrakt:	Interleukin-4 (IL-4) is a multifunctional cytokine and an important regulator of inflammation. When deregulated, IL-4 activity is associated with asthma, allergic inflammation, and multiple types of cancer. While antibody-based inhibitors targeting the soluble cytokine have been evaluated clinically, they failed to achieve their end points in trials. Small-molecule inhibitors are an attractive alternative, but identifying effective chemotypes that inhibit the protein-protein interactions between cytokines and their receptors remains an active area of research. As a result, no small-molecule inhibitors to the soluble IL-4 cytokine have yet been reported. Here, we describe the first IL-4 small-molecule inhibitor identified and characterized through a combination of binding-based approaches and cell-based activity assays. The compound features a nicotinonitrile scaffold with micromolar affinity and potency for the cytokine and disrupts type II IL-4 signaling in cells. Small-molecule inhibitors of these important cell-signaling proteins have implications for numerous immune-related disorders and inform future drug discovery and design efforts for these challenging protein targets.
Databáze:	MEDLINE
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