| Autor: |
Chen, Jinshui, Song, Yun, Bojadzic, Damir, Tamayo-Garcia, Alejandro, Landin, Ana Marie, Blomberg, Bonnie B., Buchwald, Peter |
| Zdroj: |
Journal of Medicinal Chemistry; 20240101, Issue: Preprints |
| Abstrakt: |
Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein–protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors of the CD40–CD40L interaction designed starting from the chemical space of organic dyes. For the most promising compounds such as DRI-C21045, activity (IC50) in the low micromolar range has been confirmed in cell assays including inhibition of CD40L-induced activation in NF-κB sensor cells, THP-1 myeloid cells, and primary human B cells as well as in murine allogeneic skin transplant and alloantigen-induced T cell expansion in draining lymph node experiments. Specificity versus other TNF-superfamily interactions (TNF-R1–TNF-α) and lack of cytotoxicity have also been confirmed at these concentrations. These novel compounds provide proof-of-principle evidence for the possibility of small-molecule inhibition of costimulatory protein–protein interactions, establish the structural requirements needed for efficient CD40–CD40L inhibition, and serve to guide the search for such immune therapeutics. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
