Expanding the scope of metal catalysed DNA-encoded library synthesis
Lead Research Organisation:
Newcastle University
Department Name: Sch of Natural & Environmental Sciences
Abstract
DNA encoded libraries (DELs) offer an exciting new technology for the rapid and cost-effective identification of hit compounds for drug discovery and chemical biology. Currently the libraries of compounds available to screen are limited by the range of chemistry that can be carried out on DNA-conjugated substrates. We will expand the chemistry available for generating DELs using new approaches to a range of metal-catalysed transformations, including reactions that are unreliable under traditional DEL conditions. The methodology will be applied to DEL synthesis to establish the scope and to generate libraries for screening against novel protein targets.
Planned Impact
The CDT has five primary beneficiaries:
The CDT cohort
Our students will receive an innovative training experience making them highly employable and equipping them with the necessary knowledge and skillset in science and enterprise to become future innovators and leaders. The potential for careers in the field is substantial and students graduating from the CDT will be sought after by employers. The Life Sciences Industrial strategy states that nearly half of businesses cite a shortage of graduates as an issue in their ability to recruit talent. Collectively, the industrial partners directly involved in the co-creation of the proposal have identified recruitment needs over the next decade that already significantly exceed the output of the CDT cohort.
Life science industries
The cohort will make a vital contribution to the UK life sciences industry, filling the skills gap in this vital part of the economy and providing a talented workforce, able to instantly focus on industry relevant challenges. Through co-creation, industrial partners have shaped the training of future employees. Additional experience in management and entrepreneurship, as well as peer-to-peer activities and the beginning of a professional network provided by the cohort programme will enable graduates to become future leaders. Through direct involvement in the CDT and an ongoing programme of dissemination, stakeholders will benefit from the research and continue to contribute to its evolution. Instrument manufacturers will gain new applications for their technologies, pharmaceutical and biotech companies will gain new opportunities for drug discovery projects through new insight into disease and new methods and techniques.
Health and Society
Research outputs will ultimately benefit healthcare providers and patients in relevant areas, such as cancer, ageing and infection. Pathways to such impact are provided by involvement of industrial partners specialising in translational research and enabling networks such as the Northern Health Science Alliance, the First for Pharma group and the NHS, who will all be partners. Moreover, graduates of the CDT will provide future healthcare solutions throughout their careers in pharmaceuticals, biotechnology, contract research industries and academia.
UK economy
The cohort will contribute to growth in the life sciences industry, providing innovations that will be the vehicle for economic growth. Nationally, the Life Sciences Industrial Strategy Health Advanced Research Programme seeks to create two entirely new industries in the field over the next ten years. Regionally, medicines research is a central tenet of the Northern Powerhouse Strategy. The CDT will create new opportunities for the local life sciences sector, Inspiration for these new industries will come from researchers with an insight into both molecular and life sciences as evidenced by notable successes in the recent past. For example, the advent of Antibody Drug Conjugates and Proteolysis Targeting Chimeras arose from interdisciplinary research in this area, predominantly in the USA and have led to significant wealth and job creation. Providing a cohort of insightful, innovative and entrepreneurial scientists will help to ensure the UK remains at the forefront of future developments, in line with the aim of the Industrial Strategy of building a country confident, outward looking and fit for the future.
Institutions
Both host institutions will benefit hugely from hosting the CDT. The enhancement to the research culture provided by the presence of a diverse and international cohort of talented students will be beneficial to all researchers allied to the theme areas of the programme, who will also benefit from attending many of the scientific and networking events. The programme will further strengthen the existing scientific and cultural links between Newcastle and Durham and will provide a vehicle for new collaborative research.
The CDT cohort
Our students will receive an innovative training experience making them highly employable and equipping them with the necessary knowledge and skillset in science and enterprise to become future innovators and leaders. The potential for careers in the field is substantial and students graduating from the CDT will be sought after by employers. The Life Sciences Industrial strategy states that nearly half of businesses cite a shortage of graduates as an issue in their ability to recruit talent. Collectively, the industrial partners directly involved in the co-creation of the proposal have identified recruitment needs over the next decade that already significantly exceed the output of the CDT cohort.
Life science industries
The cohort will make a vital contribution to the UK life sciences industry, filling the skills gap in this vital part of the economy and providing a talented workforce, able to instantly focus on industry relevant challenges. Through co-creation, industrial partners have shaped the training of future employees. Additional experience in management and entrepreneurship, as well as peer-to-peer activities and the beginning of a professional network provided by the cohort programme will enable graduates to become future leaders. Through direct involvement in the CDT and an ongoing programme of dissemination, stakeholders will benefit from the research and continue to contribute to its evolution. Instrument manufacturers will gain new applications for their technologies, pharmaceutical and biotech companies will gain new opportunities for drug discovery projects through new insight into disease and new methods and techniques.
Health and Society
Research outputs will ultimately benefit healthcare providers and patients in relevant areas, such as cancer, ageing and infection. Pathways to such impact are provided by involvement of industrial partners specialising in translational research and enabling networks such as the Northern Health Science Alliance, the First for Pharma group and the NHS, who will all be partners. Moreover, graduates of the CDT will provide future healthcare solutions throughout their careers in pharmaceuticals, biotechnology, contract research industries and academia.
UK economy
The cohort will contribute to growth in the life sciences industry, providing innovations that will be the vehicle for economic growth. Nationally, the Life Sciences Industrial Strategy Health Advanced Research Programme seeks to create two entirely new industries in the field over the next ten years. Regionally, medicines research is a central tenet of the Northern Powerhouse Strategy. The CDT will create new opportunities for the local life sciences sector, Inspiration for these new industries will come from researchers with an insight into both molecular and life sciences as evidenced by notable successes in the recent past. For example, the advent of Antibody Drug Conjugates and Proteolysis Targeting Chimeras arose from interdisciplinary research in this area, predominantly in the USA and have led to significant wealth and job creation. Providing a cohort of insightful, innovative and entrepreneurial scientists will help to ensure the UK remains at the forefront of future developments, in line with the aim of the Industrial Strategy of building a country confident, outward looking and fit for the future.
Institutions
Both host institutions will benefit hugely from hosting the CDT. The enhancement to the research culture provided by the presence of a diverse and international cohort of talented students will be beneficial to all researchers allied to the theme areas of the programme, who will also benefit from attending many of the scientific and networking events. The programme will further strengthen the existing scientific and cultural links between Newcastle and Durham and will provide a vehicle for new collaborative research.
Organisations
Publications
Stanway-Gordon H
(2021)
On-DNA Transfer Hydrogenolysis and Hydrogenation for the Synthesis of DNA-Encoded Chemical Libraries
in Angewandte Chemie
Stanway-Gordon HA
(2022)
On-DNA Transfer Hydrogenolysis and Hydrogenation for the Synthesis of DNA-Encoded Chemical Libraries.
in Angewandte Chemie (International ed. in English)
Castan IFSF
(2021)
On the design of lead-like DNA-encoded chemical libraries.
in Bioorganic & medicinal chemistry
Hunter J
(2021)
Highly efficient on-DNA amide couplings promoted by micelle forming surfactants for the synthesis of DNA encoded libraries
in Chemical Science
Graham JS
(2021)
Micellar Buchwald-Hartwig Coupling of Aryl and Heteroarylamines for the Synthesis of DNA-Encoded Libraries.
in The Journal of organic chemistry
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/S022791/1 | 01/05/2019 | 31/10/2027 | |||
| 2281957 | Studentship | EP/S022791/1 | 01/10/2019 | 30/09/2023 | Jessica Graham |
| Description | DNA-Encoded Libraries (DELs) are a highly promising area in the field of medicinal chemistry and chemical biology that are rapidly becoming widely established. To fully maximise their use, it is essential to carry out efficient reactions on DNA-conjugated substrates. Arylamines are privileged motifs in drug-like molecules and methods for their incorporation into DELs are required. One of the preferred methods for their preparation, the Buchwald-Hartwig coupling, does not perform well on DNA conjugates using current approaches. The research aims to apply our recently developed micellar technology for on-DNA chemistry to the Buchwald-Hartwig reaction to synthesise aryl and heteroarylamines, which will enable the preparation of diverse, high fidelity libraries of biarylamines. We aim to improve upon the previously described conversions for the Buchwald-Hartwig on-DNA reactions, which has been historically problematic with regard to broad applicability. Following a brief exploration of reaction conditions, the catalyst system of [(Cinnamyl)PdCl2] and cBRIDP using the designer surfactant TPGS-750-M was found to be effective to carry out the Buchwald-Hartwig transformation on-DNA. To further optimise the conditions, a factorial experimental design (FED) was undertaken. The FED explored the effect of amine, palladium and TPGS-750-M concentrations. From this experiment, optimum conditions were established that could be used to couple five and six membered (hetero)arylamines, as well as bicyclic systems, with the majority of substrates proceeding with >95% conversion to product. The optimised micelle-mediated conditions provide a highly efficient method for carrying out Buchwald-Hartwig coupling of DNA-conjugated aryl halides with a range of aromatic amines. The method shows broad functional compatibility and substrate scope for both reaction components, particularly for the coupling of medicinally relevant monomers, such as heterocyclic systems. Like-for-like experiments established conditions are superior to all the previous methods published. |
| Exploitation Route | The methodology developed with this funding will be of wide interest, especially useful to chemists working in the field of DNA-Encoded Libraries but also of wide interest with applications to biocompatible chemistry and organic synthesis more generally. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |