Drug Development of
TLR-mediated inflammation promotes a plethora of human diseases, including acute bacterial sepsis, chronic inflammatory diseases (e.g. SLE), cancer (e.g. certain lymphomas) and metabolic diseases, e.g. ischemia-reperfusion injury (cardiac infarction, stroke). Despite the obvious clinical need, no drugs are currently clinically available. This is –at least in part- due to the signaling mechanisms involved, which depend largely on protein interactions (highlighted with yellow dots in figure below). Such interactions are inherently difficult for targeted drug developmental approaches. In turn, while phenotypic approaches could be used, those have the disadvantage of the uncertainty of the drug target. To overcome this problem, we developed a novel phenotypic screening platform that relies on artificial activation of signaling proteins that act at different levels of the TLR pathway (green arrows in figure below). This allows us during the drug-screening campaign to focus on compounds that inhibit the TLR-specific signaling level (upstream of TRAF). We provided proof-of-concept for this approach in recent work.
OUR MAJOR OBSERVATIONS
We used a bioactive compound library and provided proof of concept for described signaling level-specific phenotypic drug screening. Moreover, using this approach we identifed a small molecule TLR signaling inhibitor scaffold (TSI), whose more detailed analysis related to structure activity relationship and mechanism of action demostrated intruiging properties.
We currently optimize described TSI scaffold, for further preclinical testing in in vivo inflammatory mouse models. We also initiated a more extensive HTS, in collaboration with the St. Jude Children‘s Research Hospital, to identify additional chemotypes for successful long-term drug development.