Quinnell Sean P, Leifer Becky S, Nestor Stephen T, Tan Kelly, Sheehy Daniel F, Ceo Luke, Doyle Shelby K, Koehler Angela N, Vegas Arturo J
Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
ACS Chem Biol. 2020 Oct 16;15(10):2649-2654. doi: 10.1021/acschembio.0c00615. Epub 2020 Sep 16.
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.
