Realising lead-oriented synthesis

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

Abstract

The pharmaceutical industry is the UK's third largest exporting sector, annually contributing £17bn to exports, and investing £4.5bn in UK research and development. The pharmaceutical industry is, however, dogged by a high failure rate (around 97%) of drug candidates, often late in the drug discovery process. A reduction in the failure rate of drug candidates would revolutionise the pharmaceutical industry (for example, a reduction in the rate of failure to even 94% would double the number of successful drugs).

The drug discovery process often begins with the screening of many (typically at least hundreds of thousands) molecules for a required biological function. Unfortunately, the active molecules identified in the high-throughput screening process are not optimised drug molecules; instead, these molecules (known as "leads") are starting points for optimisation to give final drug molecules.

There is now a clear link between the physical properties of drug candidates and their probability of successfully negotiating the development process to yield marketed medicines. In turn, the properties of drug candidates are often dependent on those of lead molecules. Unfortunately, enhancement of corporate screening collections of molecules is hampered by the poor availability of large numbers of compounds with appropriate lead-like physical properties. A recent analysis of 4.6 million commercially available compounds revealed that less than 1% had optimal lead-like properties. Furthermore, emerging synthetic methods are not, in large part, addressing this deficiency: in 2009 papers in key synthetic organic chemistry journals, only 1.8% of prepared compounds (249 from 13454) had lead-like properties. The development of robust synthetic methods for preparing diverse and novel lead-like molecules remains a significant and unmet academic challenge.

This project will realise a new approach to synthetic chemistry - lead-oriented synthesis - which will focus on the preration of large numbers of diverse small molecules with lead-like physical properties. The project will specifically focus on the development of a systematic approach to the synthesis of diverse families of novel molecular scaffolds with designed 'lead-like' properties. Crucially, specific methods will only be optimised when it has been established that the requirements of lead-oriented synthesis are directly addressed. The project will involve the identification, optimisation and demonstration of the power of a toolkit of reactions that enable the synthesis of large numbers of diverse, lead-like molecules.

Realising the full value of the research will require not only the successful execution of the approach, but the definition of a mechanism by which the technology can be made commercially available to end-users (in the pharmaceutical, and other discovery-based, industries). We have engaged, and will continue to engage, with end-users to ensure that the outputs of the project meet their specific requirements. The systematic approach will address the poor availability of lead-like compounds to end-users; will improve the physical properties of starting points and, hence, drug candidates; and will increase the probability of drug candidates negotiating the development process to become marketed medicines.

Planned Impact

The pathway to impact of the overall project will focus on (a) the definition of a pathway to commercialisation; (b) dissemination to industrial and academic scientists; and (c) improving the public's understanding of the importance of the underlying science. The investigators have a strong record of industrial engagement through collaborative studentships, EPSRC grant partnership, secondments, dissemination at leactures in industry and at conferences with industrial delegates, and leadership within RCUK-funded networks; in addition, the investigators have a strong track record of engagement with the public eg through talks at schools and education conferences; podcasts; and catalysing media up-take of their research outputs through press releases coinciding with high-impact publications.

1. Pathway to commercialisation
The proposal describes a systematic approach to generating diverse families of molecular scaffolds with designed 'lead-like' properties, addressing a demonstrated need within the pharmaceutical (and other discovery-based) industry. Realising the full value of the research will require not only the successful execution of the approach, but the definition of a mechanism by which the technology can be made commercially available to end-users. The definition of a viable mechanism will involve close working from the commencement of the project with the University of Leeds' Research and Innovation office, and Techtran (a subsidiary of IP Group PLC) that provides commercialisation services to the University of Leeds. Activities will include market assessment, protection of IP, and engagement with end-users at key stages within the project, and will lead to the identification of an effective means to bring novel, lead-like scaffolds to the market. We have requested specific funding for the time of an experienced, dedicated EKT manager (from the UoL Enterprise and Innovation Office) for market assessment and management of pathway to commericalisation (5% over 2 years).

2. Dissemination
The research will be disseminated through publication in international, peer-reviewed journals following, where appropriate, protection of IP. Funds for publications have been requested (especially for colour figures which will be required to disseminate the research effectively).

3. Public understanding of science
Nelson and the postdoctoral researchers will prepare a podcast focusing on how the project has developed new synthetic chemistry that meets the specific requirements of the pharmaceutical industry. The podcast will be uploaded to appropriate websites to allow global dissemination, and will be targeted to AS/A2 Chemistry teachers as part of a project led by Dr Annette Taylor (Schools Liaison, School of Chemistry, University of Leeds). The investigators will work closely with the University of Leeds Press Office and GSK to continue to issue press releases to coincide with high-impact publications, and will continue to engage with the general public (eg through invited visits to schools; education conferences; Café Scientifique, Headingley, Leeds). We have requested specific funding for public communication training (for the investigators and the PDRAs) and for the preparation of the podcast.

Publications

10 25 50
 
Description Synthetic methods for preparing diverse lead-like scaffolds. An open access computational tool (LLAMA) is available for the community to assess the lead-likeness of their scaffolds
Exploitation Route An open access computational tool (LLAMA) is available for the community to assess the lead-likeness of their scaffolds
Sectors Pharmaceuticals and Medical Biotechnology

URL https://llama.leeds.ac.uk
 
Description A spin-out company, Redbrick Molecular, has been established to market building blocks for drug discovery.
First Year Of Impact 2017
Sector Chemicals
Impact Types Economic

 
Description EPSRC programme grant
Amount £2,700,000 (GBP)
Funding ID EP/N013573/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 02/2016 
End 01/2021
 
Description EPSRC responsive mode
Amount £570,000 (GBP)
Funding ID EP/P016618/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 04/2017 
End 03/2020
 
Description IMI European Lead Factory
Amount € 1,600,000 (EUR)
Organisation European Molecular Biology Organisation 
Sector Learned Society
Country European Union (EU)
Start 01/2013 
End 12/2017
 
Description AZ screening 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Screening compounds
Collaborator Contribution HT screening
Impact None yet
Start Year 2014
 
Description AstraZeneca scaffolds 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Developing of new approaches to molecular scaffolds
Collaborator Contribution input into project
Impact Two papers.
Start Year 2011
 
Description Fragments 
Organisation Astex Pharmaceuticals
Department Astex Therapeutics Ltd
Country United Kingdom 
Sector Private 
PI Contribution New synthetic methods for fragment-based ligand discovery
Collaborator Contribution Steering of project
Impact No
Start Year 2017
 
Description MPI 
Organisation Max Planck Society
Department Max Planck Institute for Molecular Physiology
Country Germany 
Sector Public 
PI Contribution Screening compounds
Collaborator Contribution HT screening and follow-up biology
Impact None to date
Start Year 2014
 
Description PPIs 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research
Collaborator Contribution Expertise, assays, other assets, collaboration, secondments
Impact N/A- only just started
Start Year 2016
 
Description PPIs 
Organisation Domainex
Country United Kingdom 
Sector Private 
PI Contribution Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research
Collaborator Contribution Expertise, assays, other assets, collaboration, secondments
Impact N/A- only just started
Start Year 2016
 
Description PPIs 
Organisation Newcastle University
Country United Kingdom 
Sector Academic/University 
PI Contribution Leeds is leading an EPSRC programme grant on protein-protein interactions that involves AstraZeneca, Domainex and Northern Institute for Cancer Research
Collaborator Contribution Expertise, assays, other assets, collaboration, secondments
Impact N/A- only just started
Start Year 2016
 
Description Scaffolds for CNS drug discovery 
Organisation Takeda Pharmaceutical Company
Department Takeda Global Research & Development Centre (Europe)
Country United Kingdom 
Sector Private 
PI Contribution Developed approaches for assessing, designing and preparing scaffolds for CNS drug discovery
Collaborator Contribution Ensuring alignment with end-user need
Impact A computational tool for assessing CNS scaffolds, and syntheses of prioritised scaffolds (described in Drug Discovery Today paper aimed at end-users)
Start Year 2014
 
Description Takeda 
Organisation Takeda Cambridge Ltd
Country United Kingdom 
Sector Private 
PI Contribution Development of CNS scaffolds
Collaborator Contribution Supervision. Input to project
Impact None to date
Start Year 2014
 
Description Top down approach to molecular scaffolds 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Development of routes to diverse molecular scaffolds
Collaborator Contribution Alignment with end-user need
Impact None to date
Start Year 2016
 
Description X-ray crystallographic fragment screening 
Organisation Diamond Light Source
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to high-throughput XCHEM facility
Collaborator Contribution We provided fragments which were screened against targets at Diamond
Impact Fragment hits against epigenetic protein targets (output currently underreview)
Start Year 2015
 
Title Syntheses of lead-like scaffolds 
Description Development of practical syntheses of a range of lead-like molecular scaffolds that aligned with the needs of high-throughput screening collections for the pharmaceutical industry 
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed Commercial In Confidence
Impact None
 
Title LLAMA 
Description An open access computational tool for assessing the lead-likeness of molecular scaffolds 
Type Of Technology Webtool/Application 
Year Produced 2015 
Impact Used by about 300 chemists in industry and internationally. Used in teaching at Leeds and elsewhere 
URL https://llama.leeds.ac.uk
 
Company Name Redbrick Molecular 
Description Markets building blocks for drug discovery 
Year Established 2017 
Impact None yet
Website http://www.redbrickmolecular.com/