Discovery
of Small Molecule CD40–TRAF6 Inhibitors
Posted on 2015-02-23 - 00:00
The CD154–CD40 receptor complex
plays a pivotal role in
several inflammatory pathways. Attempts to inhibit the formation of
this complex have resulted in systemic side effects. Downstream inhibition
of the CD40 signaling pathway therefore seems a better way to ameliorate
inflammatory disease. To relay a signal, the CD40 receptor recruits
adapter proteins called tumor necrosis factor receptor-associated
factors (TRAFs). CD40–TRAF6 interactions are known to play
an essential role in several inflammatory diseases. We used in silico, in vitro, and in vivo experiments to identify and characterize compounds that block CD40–TRAF6
interactions. We present in detail our drug docking and optimization
pipeline and show how we used it to find lead compounds that reduce
inflammation in models of peritonitis and sepsis. These compounds
appear to be good leads for drug development, given the observed absence
of side effects and their demonstrated efficacy for peritonitis and
sepsis in mouse models.
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Zarzycka, Barbara; Seijkens, Tom; Nabuurs, Sander
B.; Ritschel, Tina; Grommes, Jochen; Soehnlein, Oliver; et al. (2016). Discovery
of Small Molecule CD40–TRAF6 Inhibitors. ACS Publications. Collection. https://doi.org/10.1021/ci500631e
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AUTHORS (15)
BZ
Barbara Zarzycka
TS
Tom Seijkens
SN
Sander
B. Nabuurs
TR
Tina Ritschel
JG
Jochen Grommes
OS
Oliver Soehnlein
RS
Roy Schrijver
Cv
Claudia M. van
Tiel
TH
Tilman M. Hackeng
CW
Christian Weber
FG
Fabian Giehler
AK
Arnd Kieser
EL
Esther Lutgens
GV
Gert Vriend
GA
Gerry A. F. Nicolaes