6p9e

Publication Abstract from PubMed

IL-36 cytokines are pro-inflammatory members of the IL-1 family that are upregulated in inflammatory disorders. Specifically, IL-36gamma is highly expressed in active psoriatic lesions and can drive pro-inflammatory processes in 3D human skin equivalents supporting a role for this target in skin inflammation. Small molecule antagonists of interleukins have been historically challenging to generate. Nevertheless, we performed a small molecule high-throughput screen to identify IL-36 antagonists using a novel TR-FRET binding assay. Several compounds, including 2-oxypyrimidine containing structural analogs of the marketed endothelin receptor A antagonist Ambrisentan, were identified as hits from the screen. A-552 was identified as a the most potent antagonist of human IL-36gamma, but not the closely related family member IL-36alpha, was capable of attenuating IL-36gamma induced responses in mouse and human disease models. Additionally, x-ray crystallography studies identified key amino acid residues in the binding pocket present in human IL-36gamma that are absent in human IL-36alpha. A-552 represents a first-in-class small molecule antagonist of IL-36 signaling that could be used as a chemical tool to further investigate the role of this pathway in inflammatory skin diseases such as psoriasis.

Small Molecule IL-36gamma Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis.,Todorovic V, Su Z, Putman CB, Kakavas SJ, Salte KM, McDonald HA, Wetter JB, Paulsboe SE, Sun Q, Gerstein CE, Medina L, Sielaff B, Sadhukhan R, Stockmann H, Richardson PL, Qiu W, Argiriadi MA, Henry RF, Herold JM, Shotwell JB, McGaraughty SP, Honore P, Gopalakrishnan SM, Sun CC, Scott VE Sci Rep. 2019 Jun 24;9(1):9089. doi: 10.1038/s41598-019-45626-w. PMID:31235749^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.