Discovery of First-in-Class TAK1–MKK3 Protein–Protein Interaction (PPI) Inhibitor (R)-STU104 for the Treatment of Ulcerative Colitis through Modulating TNF‑α Production

• Published in: Journal of medicinal chemistry 2022-05, Vol.65 (9), p.6690-6709
• Main Authors: Tang, Mei-Lin, Li, Haidong, Ning, Jin-Feng, Shen, Xiaoyan, Sun, Xun
• Format: Article
• Language: English
• Subjects: Animals; Colitis, Ulcerative; Mice; p38 Mitogen-Activated Protein Kinases - metabolism; Signal Transduction; Tumor Necrosis Factor-alpha
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c02198

Tumor necrosis factor α (TNF-α) 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 alternatives by targeting TNF-α 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-α production. Among them, ( R )-STU104 exhibited the most potent inhibitory activity on TNF-α production, which suppressed the TAK1/MKK3/p38/MnK1/MK2/elF4E signal pathways through binding with MKK3 and disrupting the TAK1 phosphorylating MKK3. As a result, ( R )-STU104 demonstrated remarkable dose–effect relationships on both acute and chronic mouse UC models. In addition to its good pharmacokinetic (PK) and safety profile, ( R )-STU104 showed better anti-UC efficacy in vivo at 10 mg/kg/d than mesalazine at the dose of 50 mg/kg/d. These results suggested that TAK1–MKK3 interaction inhibitors could be potentially utilized for the treatment of UC.