Rational Design, Synthesis and Evaluation of Oxazolo[4,5‐c]‐quinolinone Analogs as Novel Interleukin‐33 Inhibitors

Abstract

is an epithelial-derived cytokine that plays an important role in immune-mediated diseases such as asthma, atopic dermatitis, and rheumatoid arthritis. Although IL-33 is considered a potential target for the treatment of allergy-related diseases, no small molecule that inhibits IL-33 has been reported. Based on the structureactivity relationship and in vitro 2D NMR studies employing 15 N-labeled IL-33, we identified that the oxazolo[4,5-c]-quinolinone analog 7 c binds to the interface region of IL-33 and IL-33 receptor (ST2), an orphan receptor of the IL-1 receptor family. Compound 7 c effectively inhibited the production of IL-6 in human mast cells in a dose-dependent manner. Compound 7 c is the first low molecular weight IL-33 inhibitor and may be used as a prototype molecule for structural optimization and investigation of the IL-33/ST2 signaling pathway.

Targeting regulation of ATP synthase 5 alpha/beta dimerization alleviates senescence

“…The compound leading to the maximum increase was considered a potential hit, thereby KB1541 was found as a candidate compound (rectangle in Figure 1A). KB1541 was an oxazoloquinoline derivative and was designed to inhibit IL-33 signal transduction [9] (rectangle in Figure 1A). The detailed reaction conditions and reagents to synthesize KB1541 are described in Supplementary Figure 1.…”

“…This suggests a prominent role for IL-33 in the aging process and provides an a AGING priori basis for therapeutic strategies to reduce IL-33 as a possible intervention in patients with aging and age-related diseases. In our previous study, 20 oxazoloquinoline analogs were synthesized as IL-33 inhibitors, and 2D-NMR studies showed that the synthesized analogs were bound to structurally important residues of IL-33 [9].…”

“…In this study, using in-house compound library containing 20 oxazoloquinoline analogs designed to IL-33 inhibitors [9], we aimed to identify compounds capable of ameliorating senescence. As the role of IL-33 in senescence is not clearly elucidated, we performed a pull-down assay and identified an interaction between a novel IL-33 inhibitor and 14-3-3ζ protein.…”