Late pre-clinical development of CD40-TRAF6 inhibitors (TRAF-STOPs)


Funded period

2017 – 2019

Granted budget

€ 396,944

Indication

atherosclerosis

Therapeutic Principle

Drug

Principal Investigator

Christian Weber, Esther Lutgens, Dorothee Atzler (University Hospital of Munich)

Blocking the co-stimulatory CD40L-CD40 dyad reduces atherosclerosis. We found that the interaction between CD40 and TNF-receptor-associated factor 6 (TRAF6) is the driving force for atherosclerosis.

Using virtual ligand screening, we identified several small molecule inhibitors termed TRAF-STOPs that were modeled to bind to the CD40-binding domain of TRAF6. Two TRAF-STOPs significantly reduce existing atherosclerosis, improve glucose tolerance and insulin sensitivity in mice, and ameliorate multiple sclerosis. Here we pursue the hypothesis that these TRAF-STOPs are candidates to pass the translational pipeline towards a clinical application to treat chronic inflammatory diseases, including atherosclerosis.Dose finding studies, toxicity and pharmacological safety studies as well as pharmacodynamic studies will be performed, the pharmacological properties will be improved and the proof of the specificity of these small molecule inhibitors will be established.


Results

In pharmacokinetic studies, the candidates showed unfavorable physicochemical properties, low oral bioavailabilities and potential toxic risks, making them unsuitable for further preclinical development.