Discovery of a dual-acting inhibitor of interleukin-1 and STATs for the treatment of inflammatory bowel disease

Currently, a significant proportion of inflammatory bowel disease (IBD) patients fail to respond to conventional drug therapy such as immunosuppressants and biologic agents. Interference with the JAK/STAT pathway and blocking of IL-1 signaling are two promising therapeutic strategies for these unresponsive IBD patients. This work describes the discovery of an inhibitor 10v that not only blocks NLRP3 and AIM-2 inflammasome-mediated IL-1 beta signaling, but also reduces the expression of STAT1 and STAT5 in the JAK/STAT pathway. Importantly, 10v exhibits a significant anti-IL-1 beta effect and decreases the levels of STAT1 and STAT5 in a mouse model of colitis. As a result, a novel small molecule is identified with a dual inhibitory capacity towards both inflammasomes/IL-1 beta and STAT pathways, which supports further exploration of the therapeutic potential for IBD patients that do not respond to current drug therapy. Hybridization of active fragments led to the NLRP3-based dual inhibitor 10v, which exhibited potent inhibitory activity against the IL-1 beta and STAT pathway.