At Ubiquigent, we have applied our ubiquitin system expertise to develop a comprehensive suite of assays to support your drug discovery programmes. So, regardless of whether you’re interested in identifying or characterising deubiquitylase (DUB) enzyme inhibitors or modulators of ubiquitin ligases, or wish to exploit the ubiquitin proteasome system (UPS) to trigger the degradation of proteins – including across previously ”undruggable” targets – via PROTAC or molecular glue type approaches, we have the knowledge, assays and capabilities to support and advance every step of your drug discovery programmes.
Scroll down to explore how our Drug Discovery Screening Platform can be applied to:
The central role of ubiquitylation in diverse cellular processes makes the enzymes responsible for ubiquitylation and de-ubiquitylation very attractive drug targets to address a range of human pathologies. In the decade or more since the Nobel prize was awarded for the discovery of ‘ubiquitin-mediated protein degradation’, and more recently the clinical approval of proteasome inhibitors, there has been growing interest in exploiting other components of the ubiquitylation machinery as therapeutic targets, such as DUBs.
The development of selective DUB inhibitors has been limited by insufficient understanding of DUB biology, difficulties in establishing robust biochemical assays suitable for compound screening, limitations in cellular and in vivo models to assess DUB activity or inhibition, and the pleiotropic nature of various small-molecule DUB inhibitors (Harrigan et al., 2017). Over the last 10 years, Ubiquigent scientists have focused on building a suite of biochemical and cellular assays to identify and characterise screening hits, eliminate false positives, confirm cellular target engagement, and explore the mechanism of action of the molecules with the objective of supporting client drug discovery programmes.
Through our network of academic partners, collective experience in drug discovery and deep and extensive experience in ubiquitin system assays and medicinal chemistry, our scientists can complement your disease-specific expertise to assist you in identifying genuine drug candidates.
Deubiquitinating (DUB) 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 at [email protected]
The first compound library comprising novel small molecules designed to target deubiquitylase enzymes
Ubiquigent Ltd and The Drug Discovery Unit at the University of Dundee have jointly developed the first commercially available compound library designed to target deubiquitylase (DUB) enzymes, DUBtarget™-001.
The library has been screened against USP2 (a key target opportunity in cancer) employing our DUBprofiler™ – DUB affinity and selectivity profiling – platform. These data, as well as the physical library, are now available to access along with the option to screen the library against any of the other 37 DUB enzymes available as part of DUBprofiler to help inform starting points for drug development programmes.
We are now offering parties access to the library, associated data and further characterisation of the compound set using DUBprofiler to support their ubiquitin-system drug discovery programmes.
Ubiquigent is now seeking partners interested in gaining access to DUBtarget-001.
The library is available to be accessed in a number of ways, including:
•In its physical form for those wishing to screen it using their in-house assay platforms
•In a virtual form along with the screening data generated against USP2
•In a virtual form along with screening data generated against any other DUB enzyme(s) from the DUBprofiler panel. In this case the data will be generated upon request
If you’re interested in exploring how you can access the DUBtarget-001 DUB targeted library please contact us directly at [email protected]quigent.com
The easiest way to quickly identify novel DUB inhibitors
Screen your compounds across any or all of the 38 individual DUB targets on our panel of enzymes representative of the entire human DUB superfamily.
DUBprofiler is one of our standard services designed to help you quickly identify DUB (deubiquitylase) inhibitors. Our service is available in a range of different formats:
•DUBprofiler SPT for single-point analysis
•DUBprofiler IC50 for IC50 determinations
•DUBprofiler HT for screening larger numbers of compounds ◦As part of this service we can offer high precision and accuracy with ultra-low volume compound dispensing (down to 2.5nl) to enable addition of the assay reagents directly to the compound in 100% DMSO. This is particularly suited to screens where compound solubility and availability is a concern.
The key features of our DUBprofiler service.
•Comprehensive – ability to screen across any or all of the 38 individual DUB targets on our panel representative of the entire DUB family
•Robust – ubiquitin-rhodamine(110)-glycine substrate based-assay with multiple controls
•Flexible – screen at single concentrations (SPT) or determine IC50 values using standard 8-point half-log concentration-effect curves (IC50)
•Scalable – screen any combination of compound(s) vs. DUB
•Efficient – simple service procedure using electronic submission forms (supplied on request)
•Fast – rapid screening cycles
•Contact us and let us know what type of screen you require (SPT, IC50 or HT)
•We’ll send you an electronic submission form that lets you select the compound-DUB combination you require. We’ll also send you a set of barcoded tubes for submission of your compounds
•Our submission forms also allow you to generate as many quotations as you like based on different combinations of compound numbers and DUBs
•Once you’ve finalised your study design, email us the submission form and send us your compounds
•Once we’ve received the compounds we’ll immediately schedule them for screening and keep you updated on project progress
•Once complete we’ll send you a fully annotated data report and arrange a post project meeting to answer any questions you might have
To learn more about our DUBprofiler screening services and to discuss your specific requirements, email us at [email protected]
As pathways and functions are unravelled, new and attractive ubiquitin/UBL cascade drug discovery targets are coming to light with relevance across many key therapeutic areas.
We have now successfully developed and delivered a number of HTS-compatible assays and kits enabling leading pharmaceutical companies to conduct screening campaigns against ubiquitin cascade targets (DUBs, E3s and others) of high therapeutic value.
Projects completed include the design and development of E3 ligases HTS assays and the delivery of a reagent kit to conduct a screening campaign versus 1m+ compounds. Various hit deconvolution assays have also been delivered to dissect the mechanism of action of the hits identified from these screens.
The combination of our extensive experience in working with these pathways and our access to one of the widest collections of Research Tools allows Ubiquigent’s Custom Assay Development team to support pharmaceutical and biotechnology companies in translating discoveries into lead programmes.
Many of our assays have been developed from first principles starting with little or no data from the literature to guide the construction of the assay. Ubiquigent can research, design, manage and deliver the entire programme to help you to achieve success in your ubiquitin system HTS campaigns.
DUBprofiler™ is one of our standard services designed to help you quickly identify DUB inhibitors. DUBprofiler is available in two formats; you can choose to screen compounds at either single or multiple concentrations in either high-throughput (HT) or non-HT modes allowing studies to be run in the most efficient way regardless of compound numbers.
IDOL-E3 Ligase Assay
The E3 ubiquitin ligase Inducible Degrader of LDLR (IDOL) has recently been identified as a target of significant interest in Alzheimer’s Disease6 (AD). IDOL has a demonstrated a cellular role in the regulation and turnover of the LDL receptor (LDLR) in lipid homeostasis and to date has offered a route to the modulation of hypercholesterolaemia and cardiovascular disease1-5. Now, targeting IDOL provides a novel and exciting route to the modulation of apolipoprotein E- (ApoE) and β-amyloid- (Aβ) clearance in the brain offering potential therapeutic value in the treatment of AD6.
We have successfully developed one of the first commercially available assays to allow researchers to screen against IDOL in either HTS or non-HTS formats.
Our IDOL assay is now available to support research programmes with the objectives of identifying modulators of this putative drug target. As with our other services, the assay can be configured in HTS or non-HTS formats depending on your requirements. If you would like to explore access to our IDOL-E3 ligase assay please contact as at [email protected]
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