Journal
ACS CHEMICAL BIOLOGY
Volume 15, Issue 10, Pages 2649-2654Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.0c00615
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Funding
- Boston University
- MIT Center for Precision Cancer Medicine
- Merkin Institute Fellows Program
- National Cancer Institute [R01CA160860, P30-CA14051]
- National Science Foundation [1122374]
- Ludwig Center for Molecular Oncology
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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.
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