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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • B-Lymphocytes
  • CD40 Antigens / metabolism*
  • CD40 Ligand / metabolism*
  • Humans
  • Immunomodulation / drug effects
  • Lymphocyte Activation / drug effects
  • Mice
  • NF-kappa B
  • Protein Interaction Domains and Motifs / drug effects*
  • Small Molecule Libraries
  • T-Lymphocytes
  • Tumor Necrosis Factor-alpha


  • CD40 Antigens
  • NF-kappa B
  • Small Molecule Libraries
  • Tumor Necrosis Factor-alpha
  • CD40 Ligand