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J Med Chem. 2017 Nov 9;60(21):8906-8922. doi: 10.1021/acs.jmedchem.7b01154. Epub 2017 Oct 25.

Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction.

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Diabetes Research Institute, ‡Molecular and Cellular Pharmacology, and §Microbiology and Immunology, Miller School of Medicine, University of Miami , Miami, Florida 33136, United States.


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.

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