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 preparation 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.
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 preparation 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.
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.
Organisations
- University of Leeds (Lead Research Organisation)
- AstraZeneca (Collaboration)
- Max Planck Society (Collaboration)
- Astex Pharmaceuticals (Collaboration)
- Newcastle University (Collaboration)
- Domainex (Collaboration)
- Takeda Pharmaceutical Company (Collaboration)
- Takeda Cambridge Ltd (Collaboration)
- GlaxoSmithKline Res and Dev (Project Partner)
Publications
MacLellan P
(2013)
A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds.
in Chemical communications (Cambridge, England)
Li HY
(2014)
A convergent rhodium-catalysed asymmetric synthesis of tetrahydroquinolines.
in Chemical communications (Cambridge, England)
Colomer I
(2016)
A divergent synthetic approach to diverse molecular scaffolds: assessment of lead-likeness using LLAMA, an open-access computational tool.
in Chemical communications (Cambridge, England)
James T
(2014)
A modular lead-oriented synthesis of diverse piperazine, 1,4-diazepane and 1,5-diazocane scaffolds
in Org. Biomol. Chem.
Foley DJ
(2015)
A systematic approach to diverse, lead-like scaffolds from a,a-disubstituted amino acids.
in Chemical communications (Cambridge, England)
Doveston RG
(2015)
A unified lead-oriented synthesis of over fifty molecular scaffolds.
in Organic & biomolecular chemistry
Karageorgis G
(2015)
Activity-Directed Synthesis with Intermolecular Reactions: Development of a Fragment into a Range of Androgen Receptor Agonists.
in Angewandte Chemie (International ed. in English)
Colomer I
(2015)
Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries.
in Bioorganic & medicinal chemistry
Mayol-Llinàs J
(2017)
Assessing molecular scaffolds for CNS drug discovery.
in Drug discovery today
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 | Public |
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 | Public |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2020 |
Description | IMI European Lead Factory |
Amount | € 1,600,000 (EUR) |
Organisation | European Molecular Biology Organisation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 01/2013 |
End | 12/2017 |
Description | The Realisation of Fragment-Oriented Synthesis |
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 | 04/2020 |
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 | Academic/University |
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 |
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 Limited |
Description | |
Year Established | 2017 |
Impact | None yet |
Website | http://www.redbrickmolecular.com |