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

J Med Chem. 2022 May 12;65(9):6690-6709. doi: 10.1021/acs.jmedchem.1c02198. Epub 2022 Apr 20.

Abstract

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.

MeSH terms

  • Animals
  • Colitis, Ulcerative* / drug therapy
  • MAP Kinase Kinase 3* / antagonists & inhibitors
  • MAP Kinase Kinase 3* / metabolism
  • MAP Kinase Kinase Kinases* / antagonists & inhibitors
  • MAP Kinase Kinase Kinases* / metabolism
  • Mice
  • Protein Kinase Inhibitors* / pharmacology
  • Signal Transduction
  • Tumor Necrosis Factor-alpha*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Protein Kinase Inhibitors
  • Tumor Necrosis Factor-alpha
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • MAP Kinase Kinase 3
  • Map2k3 protein, mouse