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Late Stage Fluorination and its Applications to Drug Discovery

Periodic Reporting for period 2 - FLUDD (Late Stage Fluorination and its Applications to Drug Discovery)

Reporting period: 2019-03-01 to 2021-02-28

Modern medicine is dependent on advances in chemistry. There is spreading of infectious diseases with drug resistance growing in all countries. In addition to this the increasing cases of non-infectious diseases in an ageing population brings further challenges to healthcare. Among the challenges to developing better healthcare are: 1) lack of basic molecular level understanding of the disease biology, 2) lack of sufficiently advanced tools and methods to detect, monitor the progression and treat diseases, 3) an insufficient array of chemical tools to interrogate and validate novel disease relevant targets, 4) lack of an arsenal of both small and large molecules able to engage drug targets in vivo and thereby ameliorating diseases. Overcoming these challenges can be facilitated through stronger links between universities and the pharmaceutical companies.

The FLUDD Consortia including 2 academic and 1 industrial beneficiaries, aims to train 5 PhD students for a chemistry career in industry. With training in the development of novel late stage fluorination chemistry to populate the chemical and radiochemical space available for drug discovery. With the main focus on novel fluorine-containing fragments, molecules and biomolecules that are not commercially available but required to advance modern medicine.

The research within the FLUDD European Industrial Doctorate (EID) is focused on the following scientific and educational objectives.
The scientific objectives
- Develop novel late stage fluorination chemistry for drug discovery
- Focus on novel fluorine-containing fragments, molecules and biomolecules
The educational objectives
- To train the next generation of doctoral scientists
- Training in the practice of chemical synthesis and radiochemical methods
- Gain an in-depth appreciation of their applications in medicine
The collaborative training and research program of FLUDD is outlined in six work packages (WP). During this reporting period, the implementation of each WP and the main results from the deliverables due in this reporting period was achieved as follows:

WP1: Late stage fluorination and synthesis of fragments and molecules for drug discovery.
This reporting period which is 16months into each of the ESRs DPhil was marked by the first tangible scientific results with remarkable advances in the field of Late stage fluorination and synthesis of fragments and molecules for drug discovery- Sandrine Hell research has lead to the development of a new methodology allowing functionalization of fluorinated cyclobutane derivatives. Giulia Roagna has preliminary data for enantioselective fluorination which suggests that the methodology is able to deliver gamma-fluoroamines in high yield and excellent enantioselectivity (yield up to 90%, ee up to 94%).

WP2: Novel 18F-Radiochemistry leading to 18F labelled fragments and (bio)molecules
This reporting period which is 16months into each of the ESRs DPhil was marked by the first tangible scientific results with remarkable advances in the field of the development of Novel 18F-Radiochemistry leading to 18F labelled fragments and (bio)molecules- Claudio Meyers research in to hydro-difluoromethylation of alkenes is in preparation for publication. Tim Mollner has been performing reaction screenings for radical formation from Bal residues on a peptidic model substrate and has shown that radical formation and subsequent reactions are possible under aqueous conditions. Tim is also preparing a manuscript for submission. Tobi Arisa has shown that The synthesis of [19F][FDT] can be achieved in flow in under 20 minutes using immobilized biocatalysts for the transformation from [19F][FDG].

WP3: Metabolism studies and preclinical evaluation of new fluorochemicals for drug & diagnostic discovery
The deliverables under this work package are due in 2020. The work is currently in progress and will be described in the periodic report for this period.

WP4: Training Courses Management
From October 2017 to January 2018 all ESRs were bases at the UOXF. The ESRs completed 18 core taught modules during this time. In September 2018, the 1st FLUDD School- there were 3 taught sessions delivered by experts- representatives from KU Leuven, Invicro and Janssen. This was the first formal sessions in which the ESRs presented their results. In September 2018 all ESRs transferred from Probationer Research Student (PRS) to DPhil status.
To date ESRs have spent some time in both the university and industrial (Janssen Pharmaceuticals) settings by way of secondments. This time has been invaluable. Whilst on secondment at Janssen the students have had access to the training and expertise offered in this industrial setting. The work performed to date and the results generated so far are through collaborative efforts across academia and industry. The main scientific results achieved by the ESRs so far are in line with the reportable deliverables during this reporting period.

WP5: Coordination and Project Management
The FLUDD project started in March 2017. The Project Manager- Dr Manuja Kaluarachchi was recruited in April 2017. The Kick-Off Meeting was held in September 2017. The FLUDD consortium agreement was signed on 23rd November 2017. 5 early stage researchers were recruited and enrolled on the UOXF DPhil program by October 2017. The FLUDD Progress report was delivered on the 25th April 2018. The mid-term report was submitted in December 2018. The mid-term review meeting was held in January 2019.
In the current reporting period 5 out of 17 milestones have been met and reports for 24 out of 39 deliverables have been submitted to the European commission. All milestones and deliverables due in this reporting period have been achieved.
To date all ESRs have carried out their research between UOXF and Janssen. This has exposed them to the expertise of researchers and experts in the field from both the academic and industrial settings.

WP6: Dissemination and Exploitation of Results, Outreach Activities, Public Engagement
The FLUDD website was created within the first 6 months of the project, is regularly updates and will remain active after completion of the grant. The project can also be followed on Twitter and LinkdIn. The 2 FLUDD newsletters (with articles from ESRs and industrial partners) are available to read via the FLUDD website. FLUDD ESRs have worked with high school children and undergraduate students in outreach events. Finally 2 manuscripts are in preparation.

WP7: Ethics Requirements
The FLUDD Co-ordinators have assigned an external ethics expert to oversee these activities.
FLUDD is a unique project as it features an Oxford-Janssen alliance aimed to advance the frontiers of fluorine chemistry and radiochemistry to serve drug discovery. The FLUDD ITN stands out by merging synthesis, catalysis and radiochemistry with drug discovery with an open vista towards both small molecules and biologics.

During this reporting period FLUDD ESRs have conducted core training modules at the UOXF through the SBM, CDT program and have spent at least 6 months at Janssen). The FLUDD consortia will therefore have a great impact on their future careers giving them a dual academic/industrial culture and an international experience, encouraging innovation and development of the European academic research and pharmaceutical Industry.