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 chemical entities were screened by molecular 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 pharmacology, and genetic toxicity studies, BT-11 has a benign safety profile. With robust preclinical safety and efficacy supporting data, BT-11, a first-in-class, orally active, gut-targeting therapeutic, enters clinical trials for Crohn’s disease and ulcerative colitis in 2018.

BT-11: A new first-in-class oral therapeutic for Crohn's disease and ulcerative colitis that targets LANCL2

256th National Meeting (2018)

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