Lanthionine synthetase C-like 2: A novel therapeutic target for inflammatory bowel disease
Carbo, A., R. Hontecillas, J. Cooper, R. Gandour, M. Ehrich, and J. Bassaganya-Riera. (2015) Lanthionine synthetase C-like 2: A novel therapeutic target for inflammatory bowel disease, Digestive Disease Week, Washington D.C.
Current therapies against inflammatory bowel disease (IBD) are modestly successful and have significant adverse side effects for the long-term management of the disease. We have developed novel small molecule drugs that target the newly identified Lanthionine Synthetase C-like Receptor 2 (LANCL2) pathway, which exerts potent anti-inflammatory effects. We chemically generated 20 new chemical entities derived from parent compound 61661 belonging to the class of bis(benzimidazoyl)terephthalanilides (BTTs), and identified BT-11 as our top lead compound. Molecular modeling studies were used to predict LANCL2 binding and predictions were validated by Surface Plasmon Resonance (SPR) data, demonstrating that BT-11 strongly binds to LANCL2. Our pre-clinical efficacy IBD studies in mice showed that daily oral administration of BT-11 significantly reduces disease activity in the Dextran Sodium Sulfate (DSS)-induced model of acute colitis and the IL-10-/- mice and CD4+ T cell transfer-induced chronic colitis models. BT-11 treatment decreased leukocytic infiltration, mucosal thickening and epithelial erosion in the colon. These histological improvements correlated with decreased numbers of inflammatory F4/80+ CD11b+ macrophages and effector T helper 1 cells (Th1) as well as decreasing the infiltration of MHC-II+ CD11c+ myeloid cells in the gut mucosa. BT-11 also increased the levels of FOXP3-expressing CD4+ T regulatory cells in the gut lamina propria, spleen, and MLN, and decreased the levels of Th1 cells and RORγt-expressing CD4+ T cells in the spleen and MLN respectively. Gene expression analyses confirmed that oral administration of BT-11 up-regulates the expression of IL-10 and LANCL2, and down-regulates the expression of TNFα mRNA. To assess the safety profile of BT-11, we performed a single high-dose and a 14-day repeated daily dose studies in rats. Our initial safety and toxicology studies of BT-11 in rats confirmed its excellent initial safety profile. Rats treated with 500mg/Kg (single-dose) or 80mg/Kg over a 14-day period showed no differences in quantal functional observational battery endpoints, clinical pathology, and histopathological examination in brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum/pancreas, heart, lungs, spleen, thymus, and rib. In summary, these results demonstrate that BT-11 is a promising LANCL2-binding anti-inflammatory drug for treating IBD.