The Linchpin Strategy in the Array Synthesis of Diverse Bioactive Ligand Scaffolds

Lead Research Organisation: University of Leeds
Department Name: Sch of Chemistry

Abstract

The discovery of new drugs to treat diseases afflicting modern society is a huge challenge for chemists. For every drug that enters clinical usage, it is necessary to make and test around 10,000 candidate compounds, and total costs for the discovery programme can approach 500 million. The pressure to deliver new drugs in a cheaper, faster and more efficient manner means that chemists have to be able to deliver large numbers of drug candidates in an efficient manner. One of the techniques used to do this is so-called array chemistry, where compounds are prepared in a matrix form: for example, eight compounds of type A are simultaneously reacted with eight compounds of type B to deliver sixty four new compounds. Such an approach lends itself to automation and much of this chemistry can now be delivered efficiently and automatically by robotic synthesisers. However, there is a drawback to this array approach as it stands. Imagine the interaction of the drug molecule with its target receptor or enzyme as being like a key (the drug) fitting in a lock (the receptor/enzyme). At the start of the drug discovery process, we have the lock but no key. The chemist, like a locksmith, would take a backbone (a blank key) and decorate the backbone with different substituents (corresponding to the different arrangements of teeth on the key which code for the lock). We can therefore see that both the backbone AND the pattern are important - it is no good making hundreds or thousands of Yale keys if the lock is a Chubb design. However, until now most chemical methods for the array synthesis of large numbers of compounds as potential keys only allow chemists to work on one type of backbone at a time. It would clearly be more efficient to have a method that allows us to simultaneously vary the type of keys we make whilst still retaining the ability to alter the patterns of the teeth on the key, which will allow them to selectively interact with the desired lock . How can we achieve this?The work undertaken here will develop a new method for the synthesis of arrays, based on the use of linchpins . These are small molecules which will allow us to join together two, three or four different commercially available components in a controlled manner. Once the components are linked together, we can change the shape of the backbone by getting the individual components to react together to form ring-shaped molecules. For example, if we joined three components A, B and C together on the linchpin, we could leave the backbone alone, or we could cyclise it by joining A to B, A to C, or B to C. Each of these four possible options will have a very different shape, and hence gives us different backbones to our keys for drug discovery, as well as still being able to vary the nature of A, B and C (ie the teeth of the key). The challenge in all of this is developing methods for addition of the various components to the linchpin which are mild enough not to destroy the groups that we will use to join the components together in the cyclisation, and this is what will be studied in the current grant.

Publications

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Li HY (2014) A convergent rhodium-catalysed asymmetric synthesis of tetrahydroquinolines. in Chemical communications (Cambridge, England)

 
Description In discovering new drugs, the pharmaceutical industry makes use of libraries of compounds to find new 'leads' - i.e. compounds which have a beneficial activity and can be optimised to give new drug compounds. Unfortunately, the translation of 'leads' to marketed drugs is a lengthy and risky process, with ca. 96% of compounds failing in the discovery process. Recent work within the industry has identified that the physicochemical properties of the initial 'leads' is a big contributor to this - if the properties of the initial 'lead' are poor, then although it may be possible to tune activity, the chances of the molecule reaching market are massively reduced.

In the current grant, we have developed technologies that allow the efficient synthesis of diverse products with controllable and desirable physicochemical properties. In this way, it is hoped that drug-discovery programmes can exploit the products to develop 'leads' with appropriate physicochemical properties to the biological target/disease state, and hence improve the chances of translation to the market. The benefits to patients in terms of accelerated discovery time and reduced cost of drug discovery are just two of the benefits of this work.
Exploitation Route The availability of small molecules with diverse structures but tightly controlled and controllable molecular properties is a matter of considerable current interest to the pharmaceutical and other discovery-based) industries. We are investigating commercialisation mechanisms which will exploit the outcomes of our research to address problems of 'attrition' in drug discovery and therefore impact beneficially on the time to patient and overall drug discovery cost. Several pharmaceutical companies have expressed an interest in the commercialisation of the compounds made available by the technologies developed in the project. To this end, a licensing agreement has been signed with a global chemical supplier to deliver select classes of molecule to market.
Sectors Pharmaceuticals and Medical Biotechnology

URL http://www.chem.leeds.ac.uk/People/Marsden.html
 
Description The findings from this grant underpinned a subsequent grant from EPSRC "Realising Lead-Oriented Synthesis (EP/J00894X/1), in conjunction with GlaxoSmithKline. Together with the work carried out on grant EP/E020712/1, these results underpinned the leading role taken by the Leeds team in the European Lead Factory, a €196M public-private partnership funded through the Innovative Medicines Initiative, which aims to revolutionise drug discovery both in industry and publicly-funded or not-for-profit organisations through the creation of a high quality screening collection. For further details, please see: https://www.europeanleadfactory.eu
First Year Of Impact 2013
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description A unified strategy for scaffold synthesis
Amount £155,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 01/2011 
End 12/2012
 
Description A unified strategy for scaffold synthesis
Amount £155,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 01/2011 
End 12/2012
 
Description AstraZeneca
Amount £155,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 01/2011 
End 12/2012
 
Description AstraZeneca
Amount £155,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 01/2011 
End 12/2012
 
Description Lead-Oriented Synthesis
Amount £32,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2011 
End 04/2015
 
Description Realising lead-oriented synthesis
Amount £533,045 (GBP)
Funding ID EP/J00894X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 04/2012 
End 04/2015
 
Description Responsive mode
Amount £574,490 (GBP)
Funding ID EP/P016618/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 05/2017 
End 05/2020
 
Description GlaxoSmithKline partnership 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution The original grant was part of a call co-sponsored by EPSRC and GlaxoSmithKline. The success of the project has led to further support from GlaxoSmithKline in the form of support (financial and in kind) as project partners for a recently-awarded EPSRC responsive-mode award, and allocation of an Industrial CASE award to continue to develop the technologies uncovered in the first grant. Support for next-generation EPSRC project following on from original grant, plus Industrial CASE award. Support from GSK includes computational expertise, staff time, training etc
Collaborator Contribution Hosting researchers for extended placements; intellectual contributions to the project direction; support in terms of materials provision etc for advancement of the project.
Impact The ongoing partnership has resulted in follow-on studentship support and publications beyond the work carried out under this EPSRC award.
Start Year 2007
 
Company Name Redbrick Molecular Ltd 
Description Redbrick Molecular was jointly established by the Universities of Leeds and Sheffield to commercialise synthetic chemistry outcomes from projects at the two Universities. At the University of Leeds, the work of Professors Steve Marsden and Adam Nelson forms a key component of the portfolio, some of which arises from EPSRC-funded work. 
Year Established 2017 
Impact The company has only been established for ca. 12 months but is already generating sales revenue.
Website https://www.redbrickmolecular.com/