Discovery of First-in-Class TAK1-MKK3 Protein-Protein Interaction(PPI) Inhibitor (R)-STU104 for the Treatment of Ulcerative Colitisthrough Modulating TNF-?Production br

Tumor necrosis factor alpha(TNF-alpha) has been demonstrated to be a therapeutic target for autoimmune diseases.However, this biological therapy exhibits some inevitable disadvantages, such as risk of infection. Thus, small-molecule alternativesby targeting TNF-alpha production signaling pathway are still in demand. Herein, we describe the design, synthesis, and structure-activity relationships of 3-aryindanone compounds regarding their modulation of TNF-alpha production. Among them,(R)-STU104exhibited the most potent inhibitory activity on TNF-alpha production, which suppressed the TAK1/MKK3/p38/MnK1/MK2/elF4Esignal pathways through binding with MKK3 and disrupting the TAK1 phosphorylating MKK3. As a result,(R)-STU104demonstrated remarkable dose-effect relationships on both acute and chronic mouse UC models. In addition to its goodpharmacokinetic (PK) and safety profile,(R)-STU104showed better anti-UC efficacyin vivoat 10 mg/kg/d than mesalazine at thedose of 50 mg/kg/d. These results suggested that TAK1-MKK3 interaction inhibitors could be potentially utilized for the treatmentof UC.