Design, Synthesis,\nand Bioevaluation of Novel NLRP3\nInhibitor with IBD Immunotherapy from the Virtual Screen

NLRP3,\na crucial member of the NLRP family, plays a pivotal role\nin immune regulation and inflammatory modulation. Here, we report\na potent and specific NLRP3 inhibitor <b>Z48</b> obtained though\ndocking-based virtual screening and structure–activity relationship\nstudies with an IC<sub>50</sub> of 0.26 μM in THP-1 cells and\n0.21 μM in mouse bone marrow-derived macrophages. Mechanistic\nstudies indicated that <b>Z48</b> could bind directly to the\nNLRP3 protein (<i>K</i><sub>D</sub> = 1.05 μM), effectively\nblocking the assembly and activation of the NLRP3 inflammasome, consequently\nmanifesting anti-inflammatory properties. Crucially, with acceptable\nmouse pharmacokinetic profiles, <b>Z48</b> demonstrated notable\ntherapeutic efficacy in a mouse model of DSS-induced ulcerative colitis,\nwhile displaying no significant therapeutic impact on <i>NLRP3</i><sup><i>KO</i></sup> mice. In conclusion, this study provided\na promising NLRP3 inflammasome inhibitor with novel molecular scaffold,\npoised for further development as a therapeutic candidate in the treatment\nof inflammatory bowel disease.