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In Part II of our open access drug discovery series, Dr Wen Hwa Lee, Strategic Alliances Manager at the Structural Genomics Consortium (SGC), part of the Nuffield Department of Clinical Medicine, talks about how the medical sciences community can directly interact with SGC scientists and use their outputs to advance novel discoveries.

You mentioned in Part I that there are a lot of different assets, outputs and resources that the SGC is making available to the world – can you tell us a bit more about these? Let’s begin with the chemical probes you’ve mentioned earlier.

Creating a New Drug Discovery Ecosystem 1Sure, these are all high quality (high specificity, high potency, cell-permeable) chemical compounds that were designed to target one specific, novel human protein. We have generated 37 of these probes to date, which have been used by the global academic community to link novel targets to diseases. This process is sort of an ‘inverted pharmacology’ where you have a compound with a known target and would like to test whether the protein that is being modulated is implicated in the disease process. Many of our collaborations on these assets revolve around this strategy. The full list of our probes can be found on our website and covers several new proteins involved in epigenetics regulation.

We are also working towards a new group of chemical probes, now focussed on novel kinases, on a joint project between SGC sites here in Oxford, Frankfurt, Campinas (in Brazil) and Chapel Hill, North Carolina in the US – I’ll talk about this in part III when we’ll touch on SGC’s global strategy, but a good read about the proposal is our position paper on the topic (Knapp et al, Nature Chemical Biology 2013).

And, of course, all the activities around chemical tools and chemical biology with many excellent collaborators from Oxford made us realise that we should be harnessing all the learning to better connect all the departments and research centres in Oxford working in this area. We’ve therefore created a University-wide platform to allow identification of collaborative and exchange opportunities within our network and also to make it an external-facing showcase to external stakeholders.

I can see how these chemical probes can be helpful, but they are proteins that the SGC has decided to work on. Is there any way that medical sciences researchers can work with you and suggest genes and proteins that they have identified as potential drug targets or that might be a good intervention point to dissect biology and validation in diseases?

Creating a New Drug Discovery Ecosystem 2Very good point – and the answer to that is a big yes! We have just kicked off a new strategic grant with the Wellcome Trust in which we will be building a number of what we are calling ‘Target Enabling Packages’ – TEPs. These are, if you like, designer molecular toolkits developed for new genes/ proteins, which can be nominated by the research community. Each TEP is a set of protein-related reagents and assays (eg. purified protein, crystallographic structures, monoclonal antibodies, functional assays, etc.), which can then be used by scientists to better explore the biology of such novel proteins. We will ensure that the reagents are of a high-quality, generating reproducible results – all approved by an international panel of academic and industrial experts. We have defined four broad therapeutic areas for nomination – (i) Neuropsychiatry, (ii) Metabolic Diseases, (iii) Cancer and (iv) Inflammation. So here’s a call for colleagues who have identified new, potential targets but are finding it challenging to move the research forward due to the lack of reagents – get in touch with us either through the nomination page or by sending us a direct e-mail. We also recognize that TEP reagents can help translate rare disease research, and will shortly be putting a call out to the Oxford rare disease community – watch this space!

Here’s a question on behalf of our translational researchers, many of the SGC activities seem to be focused on early-stage: is the SGC involved in more translational and validation types of research?

Creating a New Drug Discovery Ecosystem 3Certainly – however it is such a vast area and one where we have not yet developed any internal expertise, especially where defined diseases are concerned. We have recognised this and once again working with local Oxford colleagues and our industrial partners, we have recently established a new open-source platform to use human-derived primary cells – both from patients and healthy individuals - to validate targets for new medicines. We believe this to be much more predictive of underlying mechanism of action than animal models for many diseases. This is more than just an exercise in gathering patient samples and will involve a large network of pre-clinical scientists designing novel chemical probes, working with clinicians who will provide their invaluable insights on disease biology, all alongside industrial expertise. This will speed-up the identification of disease-relevant targets. The platform – called ULTRA-DD, for Unrestricted Leveraging of Targets for Research Advancement and Drug Discovery, has been built with the help of the EU’s Innovative Medicines Initiative (IMI) and includes Principal Investigators and scientists from Oxford-based units and research institutes such as the SGC and The Wellcome Trust Centre for Human Genetics from the Nuffield Dept. of Clinical Medicine (NDM), and the Kennedy Institute and the Botnar Research Institute from the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), as well as other EU groups such as the Karolinska Institute and their Centre for Molecular Medicine, the University of Zurich and the University of Toronto. The work is centred around Inflammation and auto-immune diseases, with the explicit goals of generating probes for novel targets as well as developing and implementing novel primary-cell based assays – all in the open.

So there are a lot of existing ways that researchers here at the Medical Science Division can interact with you at the SGC! Let’s then push the envelope and ask whether the SGC is also working with other divisions and/or fields?

Another great question Alison - and let me try not to disappoint you! Indeed we have been working with collaborators in other departments, which includes statisticians, physicists and engineers to bring new technologies forward (indeed we do also have scientists from those backgrounds within our teams!). We have also been working closely with colleagues from social sciences and trying to understand the societal and economic impact of open access drug discovery platforms. But I think all of these are excellent tasters for the next part of our interview, where I’d like to share more about the more strategic efforts and programmes that we have been building with other collaborators, including patient groups, and where we are aiming to bring more impact to help other colleagues in Oxford to transform the drug discovery ecosystem.

In fact, we are organising a conference on exactly this theme – the building of a new ecosystem for drug discovery - with several exciting debates by global experts on very provocative questions! Have a look at the conference website and join us on 2nd-3rd of June!

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Courtesy of Dr Peter Canning and Ella Hughman