TY - JOUR
T1 - Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction
AU - Chen, Jinshui
AU - Song, Yun
AU - Bojadzic, Damir
AU - Tamayo-Garcia, Alejandro
AU - Landin, Ana Marie
AU - Blomberg, Bonnie B.
AU - Buchwald, Peter
N1 - Funding Information:
This work was supported by a grant from the National Institutes of Health National Institute of Allergy and Infectious Diseases (1R01AI101041, PI: to P.B.). We thank Drs. Jodie Johnson and Kari Basso from the Mass Spectrometry Laboratory at the University of Florida for their prompt and professional service.
PY - 2017/11/9
Y1 - 2017/11/9
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.7b01154
DO - 10.1021/acs.jmedchem.7b01154
M3 - Article
C2 - 29024591
AN - SCOPUS:85033363330
VL - 60
SP - 8906
EP - 8922
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 21
ER -