Selective STAT3 Allosteric Inhibitors HCB-5300 and HCB-5400 Alleviate Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, marked by persistent mucosal inflammation and structural damage. We evaluated the efficacy of HCB-5300 and HCB-5400, novel selective STAT3 allosteric inhibitors, in a mouse model of dextran sulfate sodium (DSS)-induced ulcerative colitis. Colitis was induced in C57BL/6 mice using 3% DSS in water for 5 d. HCB-5300 (25 mg/kg) or HCB-5400 (12.5 mg/kg) was administered orally during induction. Disease progression was assessed using the disease activity index (DAI), considering body weight, stool consistency, and rectal bleeding. Colon length and histopathological analyses were used to evaluate mucosal integrity and inflammatory damage. Interleukin (IL)-6 levels were quantified using enzyme-linked immunosorbent assay, and kidney pathology was assessed for systemic effects. HCB-5300 and HCB-5400 significantly mitigated DSS-induced colitis, as evidenced by reduced body weight loss, improved DAI scores, preserved colon length, and decreased mucosal damage and inflammation in the treated mice. IL-6 levels were significantly lower in both treatment groups, indicating effective STAT3 inhibition. HCB-5400 exhibited superior efficacy for most parameters. HCB-5300 and HCB-5400 are potent and selective STAT3 allosteric inhibitors with notable anti-inflammatory effects. HCB-5400's efficacy underscores its potential as a therapeutic candidate for managing inflammatory flares in IBD.