Linking Ubiquitin Research to Drug Discovery

Chemistry Overview

Targeted chemical libraries: the keys to unlock the ubiquitin system

Although the widespread use of target-focused libraries has led to the rapid expansion of novel chemistry as a research tool in drug discovery to exploit many classes of drug target, the ubiquitin system still remains a largely untapped medicinal chemistry opportunity. Protein kinases, on the other hand, have become one of the most important classes of drug targets for the pharmaceutical industry over the last decade, following on from the exploitation of kinase-focused libraries for at least the last two decades. Like protein phosphorylation by kinases, protein ubiquitylation regulates many aspects of cell function and provides a wealth of drug target opportunities across many therapeutic areas including cancer, cardiovascular, metabolism, inflammation, neurodegeneration and infectious diseases.

Following the massive breakthroughs in cancer therapy that have come about from our understanding of how to intervene in kinase signalling systems, it is becoming increasingly clear that other major cell signalling processes, such as those dependent on ubiquitin ligation and de-ubiquitination, possess the potential for further breakthroughs of perhaps similar therapeutic magnitude. The development of kinase drugs has been possible largely because of the intimate interplay of biology and focused medicinal chemistry using libraries of probe compounds designed specifically for the purpose. Along with the major advances in high-quality biological assays being driven by Ubiquigent and others, the stage is now set for a similar impact of focused medicinal chemistry – it seems that the time has now come to realise this potential.”  Dr John Harris CChem FRSC, founder of BioFocus.

To address the under-utilisation of the ubiquitin system by medicinal chemistry we have taken two approaches:

Firstly we have assembled a Reference Compound Library. These are compounds that have been reported in the literature as having activity at a range of different deubiquitinating enzymes (DUB).  As such they represent potential tools that can be used to further investigate the function of the ubiquitin system and may in themselves also represent valid starting points for drug development programmes.

The second is the development of one of the first libraries of DUB-targeted small molecules, DUBtarget™-001, developed in collaboration with the Drug Discovery Unit and the University of Dundee.

The library has been initially screened against a key DUB enzyme using Ubiquigent’s DUBprofiler platform. These data, as well as the physical library, are now available to access along with the capability to screen the library against any of the other 38 DUB enzymes available as part of DUBprofiler™ to provide starting points for drug development programmes.

If you are interested in learning more about our chemistry approach and ways to access our libraries please Contact us directly.