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
Foley DJ
(2017)
Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Horn J
(2009)
Convergent synthesis of dihydroquinolones from o-aminoarylboronates
in Tetrahedron
Horn J
(2008)
Convergent, regiospecific synthesis of quinolines from o-aminophenylboronates.
in Organic letters
Li Ho Yin
(2012)
Rhodium-catalyzed conjugate addition with functionized boronate: Divergent access to various building blocks with lead-like molecular properties
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Li HY
(2014)
A convergent rhodium-catalysed asymmetric synthesis of tetrahydroquinolines.
in Chemical communications (Cambridge, England)
Tosatti P
(2010)
Iridium-Catalyzed Asymmetric Allylic Amination with Polar Amines: Access to Building Blocks with Lead-Like Molecular Properties
in Advanced Synthesis & Catalysis
Tosatti P
(2012)
Recent advances and applications of iridium-catalysed asymmetric allylic substitution.
in Organic & biomolecular chemistry
Tosatti P
(2011)
Catalyst control in sequential asymmetric allylic substitution: stereodivergent access to N,N-diprotected unnatural amino acids.
in The Journal of organic chemistry
Tosatti Paolo
(2011)
Catalyst control in sequential asymmetric allylic substitution: Stereodivergent access to
N,N-diprotected unnatural amino acids
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
Tosatti Paolo
(2011)
Iridium-catalyzed asymmetric allylic amination with polar amines: Access to building blocks with lead-like molecular properties
in ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
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 | Public |
Country | United Kingdom |
Start | 09/2011 |
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 | Public |
Country | United Kingdom |
Start | 03/2012 |
End | 04/2015 |
Description | Responsive mode |
Amount | £574,490 (GBP) |
Funding ID | EP/P016618/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2017 |
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 Limited |
Description | |
Year Established | 2017 |
Impact | The company has only been established for ca. 12 months but is already generating sales revenue. |
Website | http://www.redbrickmolecular.com |