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

Jinshui Chen, Yun Song, Damir Bojadzic, Alejandro Tamayo-Garcia, Ana Marie Landin, Bonnie B. Blomberg, Peter Buchwald

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)8906-8922
Number of pages17
JournalJournal of Medicinal Chemistry
Issue number21
StatePublished - Nov 9 2017

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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