Discovery of a gut-restricted LANCL2 agonist for the treatment of inflammatory bowel disease.

Lanthionine synthetase C-like protein 2 (LANCL2) is an emerging target for inflammatory bowel disease (IBD). The clinical-stage agonist BT-11 (Omilancor) has shown efficacy in patients, but its symmetric structure and flexible piperazine linker raise questions about optimal binding geometry and entropic cost. We now describe SPH7050 (compound 16), in which the piperazine of BT-11 is replaced by a rigid 3-azabicyclo[3.1.0]hexane-6-yl core. Docking suggests that BT-11 engages the LANCL2 active-site entrance through hydrogen bonds to TYR-117 and LYS-164, with the second benzimidazole-picolinamide unit projecting into solvent without productive contacts. SPH7050, by contrast, is predicted to occupy a deeper subpocket, potentially forming a hydrogen bond to GLU-213 and cation-π interactions with LYS-164 and ARG-118. The compound binds LANCL2 with a KD of 3.73 μM and inhibits prostaglandin E2 (PGE2) production in bone marrow-derived macrophages (BMDMs) with an IC50 of 0.85 μM-approximately 1.1-fold more potent than BT-11 in the cellular assay. Pharmacokinetically, SPH7050 remains gut-restricted: plasma Cmax was 6.9 ng/mL after oral dosing, and Caco-2 permeability fell below 1 × 10-6 cm/s. In the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis model, SPH7050 dose-dependently reduced disease activity index and colonic inflammation, outperforming BT-11 at equal doses and matching mesalazine (100 mg/kg, QD) in efficacy with an identical total daily dose but a divided dosing regimen (50 mg/kg, BID). These data support SPH7050 as a viable next-generation LANCL2 agonist and illustrate how conformational rigidification can reshape binding geometry in a gut-restricted therapeutic context.