Abstract

Inhibition Of An E2/E3 Protein-Protein Interaction As A Novel Strategy To Counteract Autoimmune Diseases

Kamyar Hadian, Group Leader, Helmholtz Zentrum München

Small molecule drug discovery efforts have historically largely focused upon enzyme, receptor and ion-channel target classes. The protein-protein interaction (PPI) target class has been rather underexplored with respect to identifying interfering small molecules, especially when considering that they play an important role in many biological processes such as signal transduction, DNA repair and cell cycle. These important actions implicate PPIs in many diseases including cancer, autoimmune diseases and neurodegeneration. We have established several PPI assays using the AlphaScreen technology, where we primarily focus on targets from the ubiquitin-proteasome system (USP). In one particular case, we have developed an HTS assay to identify small molecules that inhibit an E2/E3 interaction. We have screened this target against 30,000 compounds of our in-house collection and were able to identify small molecules that inhibit the PPI in biochemical assays. Importantly, we can demonstrate that our selective PPI inhibitors are functional in cell lines and primary murine and human cells. Finally, we provide evidence that this inhibitor is highly effective in a pre-clinical autoimmune mouse model for Rheumatoid Arthritis. This study is a further proof that inhibiting PPIs within the ubiquitin system can modulate cellular signaling and might have the potential for the development of first-in-class therapies of many diseases.