Realising lead-oriented synthesis

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 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.