RIPK2 has gained significant interest over the last decades because of its vital functions in the control of inflammation and metabolism (Chin et al., Nature, 2002). Therefore, the development of selective NOD1-RIPK2 inhibitors would be highly beneficial in targeting inflammatory and metabolic diseases. In this project, we will perform the synthesis of potent selective NOD1-RIPK2 inhibitors. Three different drug design strategies will be developed to inhibit NOD1-RIPK2: 

  1. by occupying the ATP binding pocket of RIPK2. A screening of our own chemical library led to the identification of a hit as the first RIPK2 inhibitor blocking NOD1 inflammatory pathway and not NOD2. Pharmacomodulations allowed to obtain active molecules at the nanomolar range. Supporting by the SATT Nord de France, a series of compounds will be patented in 2025. 
  2. by degrading RIPK2. Targeted Protein Degradation (TDP) is an emerging new drug design strategy to inhibit kinases (Cromm PM et al. Cell Chem Biol 2017). We will associate one of our RIPK2 ligand to a hydrophobic tag (HyT). This bifunctional molecule will mimic a partially unfolded protein state directing RIPK2 to the proteasome for degradation by chaperone proteins.
  3. by disrupting RIPK2 interaction with its specific partner XIAP, playing an essential role in the activation of RIPK2 inflammatory pathways, responsible for its polyubiquitination (Damgaard RB et al. Mol Cell 2012). A screening, initially in silico then in vitro, of a library of Protein-Protein Interaction (PPI) inhibitors will be carried out to identify the first inhibitors of XIAP-RIPK2.

    We have identified the first selective NOD1-RIPK2 inhibitors that are active in the nanomolar. Preliminary in vivo results from mouse models of hepatic ischemia-reperfusion and DSS-induced colitis support the potential of NOD1-RIPK2 inhibitors as therapeutic agents for inflammatory diseases. Inventions disclosed in 2019 and 2023 highlighted RIPK2/NOD1 as a promising target for reducing hepatic ischemia-reperfusion injuries and treating ulcerative colitis, alongside the discovery of new selective inhibitors effective in these mouse models. With publications pending in prominent journals and a patent application in preparation, the project has attracted significant funding and academic support (I-SITE ULNE, Regional council, FRM: AAP Prix Victor et Erminia MESCLE, SATT Nord), contributing to the advancement of therapeutic strategies against inflammatory conditions. Collaborations with renowned institutions (EMBL) and the recruitment of skilled researchers underscore the project's interdisciplinary and innovative approach.