The Realisation of Fragment-Oriented Synthesis

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


Despite the rise of biological therapies, the discovery of new and improved medicinal agents to treat disease is still dominated by small molecules. The challenges in discovering a new molecular medicine are significant indeed - typically taking about 12 years from laboratory to patient, and costing of the order of $2 bn for each new drug. As a result, the pharmaceutical industry is continually looking for new approaches to improve the efficiency and productivity of the drug discovery process.

The binding of a drug to its target protein can be likened to the fitting of a key into a lock, and the design of molecular 'keys' that have the appropriate arrangements of teeth and grooves to complement the 'lock' of the protein binding site is a major challenge - particularly when one considers that the protein binding sites (and hence the molecules that need to interact with them) are generally highly complex and three-dimensional in shape. One approach to this problem, that has become increasing important over the last 15-20 years, is fragment-based drug discovery (FBDD). Here, the drug discovery process begins with fragments: very small molecules that are broadly analogous to an individual groove or tooth motif of a key. Fragments are then grown iteratively (to add more grooves and/or teeth) until promising larger and tighter-binding molecules are obtained. Although a relatively new approach, this method has already resulted in medicines that are being used clinically, for example against cancer.

Despite the remarkable rise of FBDD, significant chemical challenges for the field have been identified by industry. For example, limitations in the synthetic chemistry toolkit mean that growth of fragments is much easier in some directions that others. We will therefore expand this toolkit to enable efficient the growth of fragments in many different directions. Crucially, we will demonstrate that our fragment-oriented synthesis (FOS) toolkit can drive the discovery of ligands for pharmaceutically-relevant proteins. To ensure alignment with future discovery needs, we will collaborate with a pharmaceutical company that specialises in FBDD. We will ensure that our FOS toolkit becomes embedded in different types of drug discovery organisations to maximise the impact of the work.

Planned Impact

The non-academic beneficiaries of the research are:

1. Companies engaged in drug discovery
Over the last 15-20 years, fragment-based drug discovery (FBDD) has risen to become a mainstream drug discovery approach that is exploited by all major companies as well as many more specialised organisations. Despite the remarkable rise of FBDD, significant chemical challenges for the field have recently been highlighted by industry. We will develop a fragment-oriented synthesis (FOS) toolkit to address these specific challenges: specifically, to enable the synthesis of more three-dimensional fragments, and to facilitate fragment growth along multiple complementary vectors. To illustrate the value of our FOS toolkit, we will demonstrate that it can drive the discovery of ligands for pharmaceutically-relevant target proteins. To catalyse follow-on highlight articles in high-impact journals (eg Science, Nature and Cell series), trade magazines/websites and drug discovery blogs, we will continue to work closely with the University's Press Office to issue press releases to coincide with high-impact publications.

Realisation of the full impact of our FOS toolkit will require alignment with future FBDD needs. This alignment will be facilitated by project partnership with Astex. We will also hold a 1-day end-user workshop to which a wide range of drug discovery organisations (both industrial and academic) will be invited. Here, we will disseminate the early results from the project, and consult disparate end-users on their future FBDD needs. Following liaison with the University's research and innovation team, we will decide on the most effective mechanism to embed our FOS toolkit in many different drug discovery organisations.

2. The general public
Ultimately the main benefits of pharmaceutically-related research are societal, through the improved healthcare outcomes and/or quality of life for those patients receiving a new medication. Drug discovery is of huge interest to the general public, but the enabling role of chemistry in this process is under-appreciated. We will commission a mini-MOOC targeted at Year 12/13 pupils that imaginatively illustrates the role of chemistry in drug discovery. Leeds has already launched similar mini-MOOCs in other academic areas which have been undertaken by 1000s of school children per monthly run.

Press releases will be commissioned to publicise major publications and will stimulate media coverage that engages the general public - previous work publicised in this way from our groups has reached the national press. We will additionally continue to communicate our science in person through e.g. invited talks at schools, through presentations at education conferences and participation in the local Café Scientifique.

The accompanying Pathway to Impact document provides details of how the following specific objectives will be met:
PtI1. To sustain alignment with fragment-based discovery needs;
PtI2. To highlight the value of the FOS toolkit amongst end-users;
PtI3. To secure pathways to embed the FOS toolkit with end-users; and
PtI4. To engage the general public about the enabling role of chemistry in drug discovery.


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Description Fragment-based drug discovery (FBDD) is a popular approach to the development of new medicines, having resulted in four clinically-used molecules to date, with many more under active investigation. In FBDD, libraries of small molecules are screened against biological targets of interest - a protein associated with a disease state, for example - and those that interact with the target identified. Because the molecules screened are small, the chances of finding a 'hit' are very good, but the resulting 'hits' can only be very weakly active - far too weak to lead directly a drug candidate. In order to improve activity, we need to 'grow' these fragments to larger molecules which can have higher potency - however, this is a costly and time-consuming process which often requires making new molecules from scratch. In this project, we have developed ways to DIRECTLY grow 'hit' molecules in one or two steps, which promises to greatly accelerate this stage of FBDD. Specifically, the class of molecules we have studied (cyclic amines) are widely found in drug molecules and we have developed ways to grow them selectively at positions which were not previously readily accessible.
Exploitation Route Practitioners of fragment-based drug discovery in industry and academia will benefit from these methods, which can also be applied in other molecular discovery-based research projects. A specific example of application of FBDD to a cancer-associated kinase is under way within our research groups currently, through an EPSRC-funded PhD studentship.
Sectors Pharmaceuticals and Medical Biotechnology

Description (SYNFOS) - Synthetic toolkit for fragment oriented synthesis
Amount € 195,454 (EUR)
Funding ID 795189 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 03/2018 
End 02/2020
Description EPSRC Impact Acceleration Account (University of Leeds)
Amount £12,000 (GBP)
Funding ID EP/R511717/1 
Organisation University of Leeds 
Sector Academic/University
Country United Kingdom
Start 02/2019 
End 08/2019
Description FOS Astex 
Organisation Astex Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Development of new methods for the direct elaboration of fragments.
Collaborator Contribution Sponsorship of research aligned to the current award; expert advice.
Impact None yet.
Start Year 2017
Description FOS Manchester 
Organisation University of Manchester
Department Manchester Institute of Biotechnology MIB
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of substrates for enzymatic transformations.
Collaborator Contribution Provision of biocatalysts and expertise in screening.
Impact None yet.
Start Year 2017