Lanthionine synthetase C-like 2 (LANCL2), a novel therapeutic target for inflammatory and autoimmune diseases, and diabetes, exerts anti-inflammatory and insulin-sensitizing effects. This study reports the first LANCL2-based therapeutics for inflammatory bowel disease (IBD). New chem. entities were screened by mol. docking, then synthesized and analyzed for binding to LANCL2 by surface plasmon resonance. Piperazine-1,4-diylbis((6-benzo[d]imidazole-2-yl)pyridine-2-yl)methanone, BT-11, was identified as the lead LANCL2-binding compound for treating IBD. Oral BT-11 is effective in five mouse models of IBD exhibiting consistent downregulation of inflammatory markers and decreased presence of colonic lesions with a dependency on the presence of LANCL2. Similarly, in cells isolated from IBD patients, BT-11 decreases inflammatory markers while increasing IL-10 and FOXP3 expression. In toxicity, safety pharmacol., and genetic toxicity studies, BT-11 has a benign safety profile. With robust preclin. safety and efficacy supporting data, BT-11, a first-in-class, orally active, gut-targeting therapeutic, enters clin. trials for Crohn's disease and ulcerative colitis in 2018.