A novel retinoic acid receptor-α inhibitor, AS4040605, inhibits ILC2 activity

In recent years, many studies have focused on type 2 innate lymphoid cells (ILC2s), which are a new type of cell that produces type 2 cytokines such as interleukin (IL)-4, IL-5, and IL-13. Numerous reports have described the relationship between ILC2s and allergic diseases, and it is expected that the control of ILC2 function will lead to the suppression of allergies and other diseases. To date, however, no therapeutic drugs that directly target ILC2s have yet appeared. The purpose of this study was to identify new compounds which control ILC2 function and lead to drug discovery. We attempted to obtain ILC2 inhibitors by a phenotypic screening approach using mouse primary cells. Accordingly, we established a robust assay system to measure IL-5 production by IL-2+IL-33 stimulation using mouse lung ILC2s and conducted high-throughput screening (HTS). Approximately 30,000 compounds were examined, with structure activity relationship analysis conducted to select AS4040605 from AS3382974-related compounds. We discovered a novel compound, AS4040605, that inhibits the activity of mouse and human ILC2s and identified that its target is Retinoic acid receptor-α (RARα). With regard to mechanism of action, we also discovered that AS4040605 may act an inverse agonist of RARα.