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Institute for Advanced Simulation (IAS)

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Seminar by Dr. Kamyar Hadian

Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München für Gesundheit und Umwelt (Germany)

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15 Jul 2015 14:00
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15 Jul 2015 15:00
venue
Lecture room 2009, Jülich GRS building (16.15)

Targeting protein-protein interactions in the Ubiquitin-Proteasome System

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 cellular actions implicate PPIs in many diseases including cancer, autoimmune diseases and neurodegeneration.

We have established several PPI assay using the AlphaScreen and HTRF technology, where we primarily focus on targets from the ubiquitin-proteasome system (USP). In particular, we are interested in the PPI of deubiquitinating (DUB)/E2 enzyme interactions (e.g. OTUB1/Ubc13) as well as E3/E2 interactions (e.g. RNF8/Ubc13). These PPIs have often opposing functions in cellular processes such as the DNA damage response.

We carried out an AlphaScreen HTS campaign for OTUB1/Ubc13 by screening 30,000 small molecules of our in-house collection. The RNF8/Ubc13 assays was used for counter-screening and validation processes. Using these assays, we were able to identify small molecules that specifically and selectively inhibit OTUB1/Ubc13 interactions in vitro. Importantly, we can demonstrate that our best inhibitor is functional in its cellular context, i.e. DNA damage response. This study is a further proof that inhibiting PPIs within the ubiquitin system can modulate cellular signaling cascades in a very selective manner and might have the potential for the development of first-in-class therapies of many diseases.


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