Dundee Drug Discovery Unit Annual Report 2021

Drug Discovery Unit

Annual Report 2021

Excellent science only happens with excellent people.

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Drug Discovery Unit

Foreword First of all, and most importantly, a huge thank you to everyone in the Drug Discovery Unit (DDU) in the School of Life Sciences at the University of Dundee: 2021 has been a difficult year, disrupted by waves of Covid-19 and changing guidelines. But, despite this, the progress made in every portfolio and by every cross-cutting technology team, as set out in this report, has been simply outstanding.

Excellent science is the oxygen, the bread and butter (and the caviar) of drug discovery. From its inhouse biology, and that of its collaborators, through its screening and characterisation technologies, computational, analytical and synthetic chemistry to its molecular pharmacology – excellence and true interdisciplinary working is writ-large across the DDU. The developments of 2021 in, just for example, molecular interactions, AI-driven predictions, platebased chemistry, and image-based drug distribution studies are profound. They are part of a healthy continuum of innovation that keeps Dundee at the toptable of academic drug discovery. I salute all involved and look forward to even more innovations in 2022!

Excellent science only happens with excellent people, and excellent people have to be given the tools they need to excel. This requires resources. This past year has been extraordinarily successful in securing funding

for DDU activities – over £20 million. This includes major funding for the Wellcome Centre for Anti-Infectives Research, in which the DDU is the drug discovery engine, and for the kinetoplastid, apicomplexan and TB portfolios. Preparing the applications for these peerreviewed awards is very complex and time consuming and all involved deserve enormous credit.

The past year has also seen fantastic efforts in public engagement and in training – despite Covid limitations.

It has also seen the DDU senior leadership team design and launch more leadership and training opportunities for staff. It is vital that the DDU continues to embrace and extend equality, diversity and inclusion principles and actions.

I want to congratulate Ian Gilbert for his election to the Academy of Medical Sciences and David Gray for his British Empire Medal in recognition of his selfless efforts in helping set up and maintain Covid-19 PCR testing for Scotland.

I had the privilege of being one of the co-founders of the DDU in 2006. I could not have dreamed that it would grow and develop in the way that it has. I am both proud and humbled by its success; a success in which everyone, past and present, has played their part.

However, it would be remiss in the extreme not

Annual Report

to acknowledge Paul Wyatt who has been Head of the DDU since its founding and who has, with his colleagues, grown it from 15 to 130 dedicated staff and introduced massive innovations into the way we prosecute early-stage drug discovery at the University of Dundee. Sadly, for us, Paul will move on in 2022 leaving a legacy of a highly functional and functionalised Drug Discovery Unit with solid succession plans. We all wish Paul every success in his next endeavour. Another loss in 2022 is Julie Brady, the DDU’s dedicated business development manager who has been with us for over eight years. She has tirelessly opened-up developing funding, commercialisation and communications opportunities for the DDU. She will be sorely missed and again our thanks and best wishes go with her.

In summary, I congratulate all in the DDU for a spectacular year and look forward to seeing their progress.

Sir Mike Ferguson Regius Professor of Life Sciences University of Dundee

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Drug Discovery Unit

Contents Foreword 4 2021 Summary

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Case Study

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Introduction to the DDU

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What we do

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Anti-Infectives Drug Discovery

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Innovative Targets and Pathways

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How we do it

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Translational Funding

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Impact

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2021 – A year of continuing challenges

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Accelerating Innovation in Drug Discovery

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Portfolio Highlights

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Kinetoplastid Portfolio

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Apicomplexan Portfolio

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Tuberculosis (TB) Portfolio

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Coronavirus Portfolio

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Innovative Targets Portfolio

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Spotlight on our Molecular Interaction Team (MIT)

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Governance and Structure

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DDU structure

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Advisory Boards and Committees

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Career Development

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Finance

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Closing Remarks

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Drug Discovery Unit

Summary As we celebrate 15 years of the DDU we can be proud of our achievements over what can be considered a relatively short period of time in the world of drug discovery and development. It gives us tremendous pleasure to report that the results from the first in human (FIH) studies with our malaria candidate, now in clinical development with Merck, have been published, showing a single dose cure at a well-tolerated dose - thelancet.com/infection, published online October 26, 2021 doi.org/10.1016/S1473-3099(21)00252-8. This huge success in going from fundamental discovery science to a drug in successful clinical trial, highlights the capability and impact of the DDU, working with partners, in translating world-class discovery research into new de-risked targets and candidate drugs.

2021 also saw Pacylex Inc. initiate First in Human studies with PCLX-001. PCLX-001 is a small molecule, first-in-class N-myristoyltransferase (NMT) inhibitor, originally developed by the DDU (DDD86481) as part of a program, funded by Wellcome, to treat African sleeping sickness. Pacylex is developing PCLX-001 to treat leukaemia and lymphoma. PCLX-001 is the lead drug in a new class of NMT inhibitors, enabling Pacylex to exploit NMTs as new mode of action clinical targets for cancer treatment. Pacylex has also received regulatory authorisation to begin clinical studies for Non-Hodgkin’s lymphoma and solid tumours in Canada.

The DDU has firmly established itself as the UK’s leading academic drug discovery engine working across multiple therapeutic areas, now with four clinical candidates (for malaria, cancer and two for visceral leishmaniasis) and compounds nearing preclinical candidate selection in both TB and cryptosporidiosis.

Our Innovative Targets Portfolio continues to deliver sustainable partnerships with industry and we initiated an exciting new collaboration with Swedish biotech Beactica Therapeutics to develop novel PROTAC degraders of WRN helicase as a potential anti-cancer therapy. The target biology is under the direction of Professor John Rouse at the University of Dundee and the program brings together chemists and structural biologists from the DDU and Beactica to drive the translation.

The Innovative Targets Portfolio provides a crucial link between the DDU, the University of Dundee and the UK life sciences sector and is a critical component of Dundee’s commitment to translation of innovation for public benefit. The University of Dundee’s reputation for excellence in life sciences commercialisation has been recognised in the ‘State of Innovation’ report

by Clarivate Analytics in 2017, Octopus Ventures Entrepreneurial Impact Ranking, 2019 and the GovGrant Universities Spin-Out Report 2021. The University continues to build upon its world-class expertise and reputation in life sciences research and drug discovery with the creation of a new life sciences Innovation District including a 5800 sqm Innovation Hub to support the scale up and expansion of substantively invested new life sciences companies.

During 2021 the DDU has renewed research grant funding to support our translational activities in kinetoplastid diseases, TB and malaria and secured support to initiate a collaborative project on schistosomiasis. The DDU has taken over the lead of the Structure-guided Drug Discovery Coalition (SDDC), funded by the Bill & Melinda Gates Foundation to deliver new drug targets for TB and malaria. We have also renewed our collaboration with Bukwang Pharma seeking novel therapies for Parkinson’s disease.

Leading

the translation of life science research

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Maintaining staff morale across the DDU as we continue to operate under challenging conditions brought about by COVID has led to the introduction of virtual cross-portfolio and cross-discipline events to maintain good interactions across the DDU. We remain enthused and encouraged by the passion that our teams have for the diseases we work on, in particular, those that disproportionally impact lowand middle-income countries.

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A key focus for 2021 has been on our next generation of leaders and investing in the future sustainability and development of the DDU. This involves success in securing research funding as well the necessary leadership skills and technical expertise. Our extended leadership team is working closely with our senior leaders to build the necessary individual skills, experience and global reputation to underpin our succession plans.

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Another area of progress is in our COVID portfolio. We are progressing our methyltransferase targeting project in partnership with pharma and other partners within the Innovative Medicines Initiative (IMI) Corona Accelerated R&D in Europe (CARE) consortium. The project has the potential to yield a first-in-class therapeutic targeting viral RNA processing. The current pandemic has provided an opportunity for the DDU to consider broadening its remit to support other viral indications of global concern.

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At a glance → Malaria kills over 600,000 people annually, the majority children under five. → DDD107498 discovery won MMV’s Project of the Year 2014 → A phase 1b human clinical study of single oral doses of M5717 demonstrated single dose cure and was recently published in The Lancet

→ Merck KGaA licensed DDD107498, renamed M5717, as their flagship anti-malarial for pre-clinical and clinical development.

DDU compound DDD107498 can cure malaria with a single dose costing less than

$1

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Case study Invention and deployment of single dose cure and chemoprotective agent for malaria Malaria is a debilitating parasitic disease posing a risk to nearly half the world’s population. The predominant malaria parasite, Plasmodium falciparum, has developed resistance to current treatments and new drugs are therefore urgently needed to effectively treat and eventually eradicate malaria. New anti-malarials must meet several requirements: (a) novel modes of action with no cross-resistance to current drugs; (b) single-dose treatments with activity against bloodstage disease; (c) activity against liver stages that can prevent disease (chemoprotection or prophylaxis); (d) compounds active against the sexual stages (gametocytes) to block transmission of malaria.

The DDU has been working closely with Medicines for Malaria Venture (MMV), a not-for-profit public-private research and development (R&D) partnership, since 2009 to identify new treatments for malaria. Working with collaborators in Columbia University, USA, and the Wellcome Sanger Institute we delivered DDD107498, a compound that acts through inhibition of protein synthesis, with parasite translation elongation factor eEF2 as its target. After treatment with DDD107498 the parasites cannot make essential proteins and die.

The completely novel mode of action of DDD107498 make it a very attractive prospect for further development. Crucially, it is effective against parasites resistant to current drugs at a cost of goods within MMV’s goal of $1 per treatment.

In 2014, MMV formally declared DDD107498 as a candidate for preclinical development. The discovery won MMV’s Project of the Year 2014.

At the time MMV said: “This molecule has caused a stir… DDD498 has potent activity against multiple stages of the malaria parasite’s lifecycle, giving it the potential to cure and stop the spread of the disease as well as protect people, all in a single-exposure”.

Thanks to the attractive properties of DDD107498, MMV was able to successfully partner the compound with Merck KGaA where it was licensed as their flagship anti-malarial for pre-clinical and clinical development and renamed M5717. The compound successfully completed human safety clinical trials (phase 1a) in 2018 and, remarkably, demonstrated single-dose cure in a human volunteer infection model of malaria, in a second human 1b trial, This has just been published in the Lancet (doi.org/10.1016/ S1473-3099(21)00252-8) . Together, these studies demonstrate that M5717 supports the potential for single-dose administration and suggests that future combination therapies of M5717 with a partner-drug are warranted to mitigate the risk of resistance.

The Head of Merck Global Health Institute explains the impact on the company: “The DDU’s work to identify DDD107498 and characterise it and its safety profile meant that Merck were provided with a highly effective drug candidate ready for clinical trial. The DDU de-risked the process and provided the incentive for us to proceed to clinical development in 2017 with a new drug for malaria that we would have been very unlikely to develop independently. This also allowed Merck to develop our malaria portfolio”.

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Drug Discovery Unit

Introduction to the DDU The Drug Discovery Unit (DDU) is unique: a complete ‘biotech-style’ drug discovery engine delivering candidate drugs, derisked drug targets and commercialisation opportunities across multiple disease areas within a UK university.

We have two core areas of activity

Our mission

Anti-Infectives Drug Discovery

To exploit the potential of unexplored therapeutic target pathways and turn innovative discovery science into candidate medicines that will make a difference to patients’ lives.

In low- and middle-income countries (LMIC), more than 450 million people are at risk from diseases such as malaria, leishmaniasis, Chagas’ disease and cryptosporidiosis.

What we do The DDU tackles unmet medical need through small molecule drug discovery, bridging the gap between academic scientific research and commercial and charitable drug discovery and development. We draw on the best of these worlds, employing highly skilled, experienced scientists from academic and pharmaceutical industry backgrounds, with a professional, pioneering approach to our work.

→ Anti-infectives drug discovery → Innovative targets and pathways

Existing treatments can be expensive, difficult to administer, unsafe and/or increasingly ineffective as the parasites that underlie these conditions develop resistance.

Our overall goal is to generate lead compounds suitable for further development with our partners and, ultimately, to identify candidate molecules for entry into pre-clinical and clinical development.

Annual Report

Innovative Targets and Pathways

How we do it

Disease experts and academic researchers continue to discover new biological processes which could be drug targets for major clinical indications. However, these targets are very often not sufficiently validated for licensing into pharmaceutical company portfolios or for spin-out company investment. The DDU is committed to bridging this gap by developing chemical assets that can advance our understanding of the underpinning biology and, ultimately, establish proof of concept in gold standard pre-clinical models of disease.

We collaborate with partners globally to identify potential drug targets, lead compounds, candidate drugs and novel tools and approaches to develop improved treatments for a wide range of debilitating and deadly diseases. The DDU has the full repertoire of professional, industry-standard expertise and infrastructure required for early-stage drug discovery.

These disciplines work together closely in an integrated management structure.

Medicinal chemistry

Bioinformatics

→ Design, synthesis and development of drug-like compounds

→ Management and analysis of biological data

→ Invested in new synthetic design and synthesis techniques

→ Statistics, computational science, databases, algorithms → Building 3D models of protein structures

→ State-of-the-art equipment and methodology

Drug metabolism and pharmacokinetics

Structural biology and biophysical techniques

→ Integrated DMPK group

→ State-of-the-art protein crystallography infrastructure

→ Supports hit and lead optimisation programmes → Industry standard in vitro and in vivo assays

→ BLI, SPR, NMR hit finding and validation techniques

→ High-value mass spectrometry equipment to analyse biological samples

Hit discovery

Computational drug design

→ Comprehensive range of liquid handling and detector technologies; including nanolitre acoustic dispensing

→ Druggability assessment of protein targets

→ Target-based and phenotypic screening technologies

→ Virtual screening

→ Bespoke compound libraries → Multiple screening modlities and instruments

→ Selection of compound libraries → Analysis of screening hits → Compound design using protein structure → Optimisation of drug-like properties in design

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Drug Discovery Unit

Translational Funding Strong partnerships with organisations funding scientific research for drug discovery has been fundamental to our success. We are grateful to Wellcome, the Bill & Melinda Gates Foundation, Medicines for Malaria Venture, the Medical Research Council of UKRI, and the Drugs for Neglected Diseases initiative, amongst others, for their continued support and encouragement. We align our research strategies and infrastructures with our funder’s aims and objectives and, together, deliver on our joint objectives to control or eliminate debilitating and fatal diseases.

Impact Our impact is recognised not only by the progression of our compounds into pre-clinical and clinical trials with our partners but also by supporting partner academic groups to secure research grant funding to further explore disease biology using the tool molecules we produce.

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compounds in clinical development

£100m Secured more than

in research funding

130 6

experienced translational scientists

newcos enabled with DDU assets

Annual Report

2021, a year of continuing challenges Despite COVID restrictions during 2021, we have continued to be productive with hybrid home and on-site working and booking systems to access space and equipment. Indeed, our staff survey reflected improvements in productivity and efficiency across several areas of activity, leading to the launch of a new flexible working policy.

In terms of funding, we were facing a potential cliff edge with many of our strategic funding agreements due for renewal within 2021. Along with our new COVID portfolio, enabled by the Bill & Melinda Gates Foundation, we have successfully renewed support from Wellcome for the Wellcome Centre for Anti-Infectives Research (WCAIR) and a continued collaboration with GSK, Tres Cantos for our Kinetoplastids portfolio. In addition, renewed funding from the Bill & Melinda Gates Foundation for our TB team will support numerous ongoing collaborations with the TB Drug Accelerator (TBDA) to drive delivery of lead compounds into preclinical development.

Strategically, our ambition is to maintain the DDU at its current size which requires investment of circa £12M p.a.to support staff levels and associated equipment, technology and consumable needs. We will seek to increase the diversity of our funding by building relationships with potential partners and funders interested in tackling diseases of the highest medical need. In terms of delivery, our objective is to deliver on average one preclinical candidate and one commercial licence or spinout company per year.

An ongoing challenge is in the retention and recruitment of drug discovery experienced scientists in a currently buoyant marketplace. We are working with the University to implement more flexible working conditions and offer competitive employment packages. We are also committed to providing an enjoyable, rewarding and intellectually challenging place to work with recognition and reward for good work and behaviours at team and individual level.

With our core focus to address Neglected and Tropical Diseases we have initiated a new research programme in schistosomiasis (also known as Bilharzia). Funded by Wellcome, this project is a collaboration with colleagues in the Universities of Aberystwyth and Cardiff.

As we enter 2022, the focus for the DDU is to maintain excellent standing and recognition in the UK and globally – exemplified by our delivery of innovation, quality of science shared in peer-reviewed papers, successful collaboration and partnerships, and the delivery of preclinical drug candidates.

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preclinical candidate per year

Multiple

ongoing BioPharma collaborations

commercial licence/spinout per year

Embedding new technologies across portfolios

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Drug Discovery Unit

Accelerating Innovation in Drug Discovery The DDU is a critical component of the Wellcome Centre for Anti-Infectives Research (WCAIR). The WCAIR mission, with its partners, is to be at the cutting edge of how to prosecute drug discovery for major infectious diseases affecting low-and middle-income countries. Our ambition (with a horizon to 2030) is to radically increase the rate and success of delivering drug candidates by fundamentally redesigning drug discovery processes for these diseases. We work with key opinion leaders from across disciplines to critically assess and apply new approaches and technologies in our research and drug discovery groups.

Despite significant advances, the following continue to hamper global drug discovery pipelines for major infectious diseases: 1

Lack of validated targets to support target-based approaches;

2 Sub-optimal paradigms for drug discovery (eg a lack of understanding why compounds work or not in decision-making disease models); 3 Sub-optimal computational methods.

A common response to these deficiencies and the resulting widely reported high attrition rates has been to simply make and test more compounds in an attempt to deliver successful drugs. However, this legacy model of chemistry at the core with satellite disciplines linked through data management channels is neither optimal nor sustainable in resource poor settings. Therefore, we are seeking to fundamentally improve our approach to drug discovery by re-thinking the process, optimising and better integrating all component parts and underpinning it with world-class discovery research.

Core to achieving this is gaining a better understanding of disease biology, including: where the pathogens are found, their physiological state, and the drug targets that will clear pathogens regardless of their locality or biological state.

This greater understanding allows improved: → Compound Design: Predicting the behaviour of compounds before they are made, based on coherent data sets to train algorithms, and computational expertise and methods to derive them. → Chemistry Design: Improved and broader methods to rapidly and efficiently make optimally designed compounds at a scale to address key project goals. → Assay Design: Appropriate in vitro assays and animal disease models that are predictive of clinical outcomes. → Data Analysis: Use all available data to build better design models through machine learning.

By tackling these issues, we are impacting the whole drug discovery continuum to accelerate project progression (or closure) and thus increase the flow of candidate drugs. These improvements are available to others, through collaboration, knowledge exchange and training. Although WCAIR’s current focus is on leishmaniasis, Chagas’ disease and cryptosporidiosis, the ’toolbox’ of methods and approaches under development is applicable to other diseases.

Annual Report

To achieve these goals, the DDU and WCAIR are addressing three main research themes: 1

Gaining a deeper understanding of parasite biology and building and applying new tools to delineate the modes-of-action of potential therapeutics. We have significantly advanced our understanding of parasite biology, compound mode of action studies and the identification of new drug targets by improving our ability to manipulate pathogens at both genomewide scale and at precision level, and by advanced chemical proteomics and other methods.

2 Defining critical paths and assay cascades predictive of human efficacy. We have developed better assay cascades that predict animal model and clinical efficacy and processes to understand why compounds do or don’t work against pathogens in clinically relevant states and body compartments.

These and future advances will radically improve decision making, allowing the faster triage of compound series that are unlikely to work and a focus on series with suitable computationallypredicted and measured properties.

Specific examples include New assays for Chagas disease screening cascade.

We have developed an in vitro wash-out assay, that detects the small population of Trypanosoma cruzi (T. cruzi) parasites that are less susceptible to compounds.

This assay is the best in vitro predictor of outcome in animal models and is now the gatekeeper to moving compounds into animal model studies. It has been adopted by others e.g. DNDi, Novartis and University of Washington.

Parasite distribution in Chagas disease. To understand parasite distribution before and after drug treatment, we have implemented whole organ clearing protocols, CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails) in conjunction with transgenic parasites expressing fluorescent proteins to identify where ‘persister’ parasites reside at end of drug treatment and prior to reactivation and redistribution. This will provide the granularity on drug distribution properties required for treatment success.

Parasite Imaging. For Chagas disease, we have developed matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) imaging protocols for whole animal sections to understand the tissue distributions of key compound pairs. Based on initial whole animal images, specific organs/tissues will be imaged at higher resolution as directed by the parasite distribution.

Compartmental PKPD modelling. Using a set of compounds with different modes-of-action and available PKPD data in the acute and chronic mouse models of Chagas disease, a simple PKPD model (treating the body as a single compartment) has been built in Simbiology which successfully predicts the behaviour of selected compounds in animal models from in vitro data.

Parasite and drug distribution. Spatiotemporal variation in parasite distribution during Chagas disease dictates the need for a wide drug distribution. Tools predicting compound distribution are therefore valuable to prioritise compounds for mouse efficacy experiments.

Predictions of tissue/organ partition coefficients (Gastroplus, Simulation Plus) have been validated and these predictions are now placed early in projects to prioritise compounds with limited or no P-gylcoprotein (PgP) interaction for animal disease model experiments.

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Drug Discovery Unit

3 Applying and integrating state-of-the-art approaches to radically improve the Design-TestMake-Analyse cycle to accelerate drug discovery projects to key milestones or project closure.

Specific examples include Design. We are developing the use of Fragment Molecular Orbital – Quantum Mechanics (FMO-QM) methods to better predict the binding affinities of compounds to target proteins. The method has been validated on external target datasets, where predicted and measured target activities were all within < 0.5 kcal/mol (correlation R2 >0.8). In house innovations have decreased compute time >1000fold to <5 minutes/compound/central processing unit (CPU) compared to standard methods. The speed and accuracy of these predictions fundamentally change how they can be used in drug discovery projects. We are developing relationships with colleagues in world leading universities to further develop our capabilities in machine learning and artificial intelligence.

Make. Our Synthetic Methodologies Team (SMT) works with partners and advisors to fundamentally improve how we make and test compounds. Integrated into all DDU’s drug discovery projects, the SMT carries out specialist activities (e.g. route scouting and scale up) and establishes new technologies, e.g. array chemistry run in 96/384 well plates and using flow chemistry.

The SMT is also introducing an expanded repertoire of synthetic approaches to our medicinal chemistry teams, including biotransformations. Our ability to make and test multiple compounds without purification, to rapidly explore compound series in parallel and to supply data to build computational models, identifies key structureactivity hot spots and eliminates the needed to purify, analyse and format thousands of inactive compounds.

Altogether, this produces a >20-fold increase in compounds made and tested per chemist and a 250fold decrease in the amounts of synthetic intermediates required; only compounds of interest are purified and re-synthesised for full characterisation.

Test. We have expanded of our range of assay systems including mass spectrometry-based high throughput screening systems. The latter directly measures substrate and/or product without the interference problems inherent with indirect readouts. This has enabled screening of un-purified compounds without compromising quality and allowed us access to a wider range of target biochemistry.

Pathogen hopping strategies. We are efficiently repositioning chemical matter for a target developed for one pathogen into others. For example, a lysine tRNA synthetase inhibitor series identified for malaria has yielded leads for cryptosporidiosis (in late lead optimisation), Chagas disease (used to de-validate the target) and TB (in drug candidate selection).

Enabling structure-based drug discovery. To increase success rates for producing key proteins, we have introduced high throughput construct design and expression system testing. Also, in collaboration with Diamond Light Source, Harwell, we have established and optimised X-ray fragment screening of thousands of crystal soaks (XChem) to initiate structure-based projects.

Analytical and Physiochemistry. We have established and incorporated new assays to determine the physical properties of compounds, improving decision making within compound optimisation. These include RelSOL (LCMS based kinetic solubility assay), a modified CHI logD lipophilicity assay (chromatography based) and a FaSSIF solubility assay (to determine compound solubility in simulated gastric fluid).

Annual Report

Activities that address the three research themes MoA studies on compounds with desired profile (MoA Group)

3.3.1 Study hostpathogen-drug interactions

Study of population heterogeneity

Parasitology understanding

2.1 Gene editing

Relevant in vitro models

3.3.1, 3.3.2 In vitro live-imaging PK/PD assays

Disease relevant in vivo models

Appropriate MoA

Understanding PK/PD drivers

PK

3.3.2 Live cell imaging

Back-translation from clinical data

Parasite localisation 3.1 Cleared tissue imaging in mouse model

3.1 Appropriate in vitro assays for tissue distribution

Metabolism

3.3.1, 3.3.2 In vitro live-imaging PK/PD assays

Location of disease-relevant parasites in vivo

Alternative administration options

Translation to humans 4.4 Alternative formulations for oral dosing

1.2 Expansion of chemical space

3.4 3D models/ organoids

DRUG

Compound tissue distribution

1.1 Alternative screening approaches

3.3, 3.4, 3.5 Screening cascade development

3.2, 3.4, 3.5 Model development

3.3.1, 3.3.2 PK/PD modelling Whole body imaging

3.2 3.3.2, 3.4 Increasing Machine physiological learning and relevance of AI for image in vitro assays analysis

4.4 Alternative administration routes

Screening 1.3, 2.3 Alternative drug discovery approaches 4.2 Austomated route design 4.3 Efficient synthesis and purifiction methods

TEST MAKE

ANALYSE DESIGN 4.1 Predictive compound design

2.2 Structural biology

3.1 In vivo population heterogeneity

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Drug Discovery Unit

Portfolio highlights Kinetoplastid portfolio Chagas disease The kinetoplastid portfolio aims to develop much needed new medicines for Chagas disease. Chagas disease is a chronic disease that results from infection with Trypanosoma cruzi protozoan parasites. It affects millions of people in Latin America and beyond, and is a major cause of debilitating, and sometimes deadly, heart disease. ​ Portfolio overview Our work in Chagas disease ranges from basic biology to pre-candidate selection. Main areas of activity are: → Study of persister parasites. Parasites that are less susceptible to drug treatment are a key challenge in Chagas disease drug discovery. We aim to better understand their biology, to find markers of the persister state and find new targets for these forms.

Key highlights for 2021 → GSK245/DDD143 progressed to Phase 1 clinical trials → Candidate level efficacy achieved for several compounds in our 4WAY001 lead optimisation series → Identification of multiple new series for entry into hit to lead chemistry

→ New methodologies to improve the drug discovery path for Chagas disease: a major aim is to better understand the compound profiles required for Chagas drugs, this includes the in vitro profile, mode-of-action, and in vivo understanding of PK/PD drivers.

We use a science-directed approach to achieve this, often through development and implementation of new methods and approaches. → New pre-clinical candidates for Chagas disease.

The 4WAY001 series is our most advanced series, which shows clinical level efficacy in an animal model of chronic Chagas disease. The main focus of the lead optimisation programme is now to bring together all required properties to achieve precandidate selection.

Annual Report

Hits →

Hit to lead →

Lead optimisation →

Pre-Clinical →

Clinical →

Visceral Leishmaniasis – GSK899/DDD651 Visceral Leishmaniasis – GSK245/DDD143 Chagas’ Disease – 4 WAY001 Chagas’ Disease – 4WAY backups Chagas’ Disease – multiple series

Collaborators and funders:

Fundamental biology

New technologies

→ Study of Trypanosoma → Novel in vitro assays cruzi persisters → New methods for parasite and compound distribution studies in vivo

Improving drug discovery

Drug discovery for Chagas disease

→ Develop and improve → Develop new predrug discovery cascade clinical candidates for Chagas disease for Chagas disease → Increase efficiency and reduce timelines

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Drug Discovery Unit

Apicomplexan portfolio Malaria and cryptosporidiosis

Portfolio overview

Our team works to develop new treatments for malaria and cryptosporidiosis, caused by apicomplexan parasites. These diseases disproportionally affect children in low- and middleincome countries, particularly in Africa. There is no effective treatment for the diarrheal disease caused by Cryptosporidium in malnourished infants. Resistance to current malaria treatments is spreading, increasing the need for new medicines.

Our projects have expanded from hit identification to pre-candidate selection:​ → We lead the Structure Drug Discovery Coalition (SDDC) which applies structure-based drug design to deliver early lead series for malaria and TB.​ → We have a lead optimisation project for malaria in collaboration with Eisai and MMV and a more advanced late lead profiling project for cryptosporidiosis in collaboration with the University of Vermont and Eisai.

Expanding outside of ‘the apicomplexan world’ we have initiated a new project to help establish a drug discovery pathway for schistosomiasis, an infectious disease cause by worms that affects 250 million people each year. This may develop into a new schistosome portfolio as we build expertise in the field.

Key highlights for 2021​ → M5715 (DDD498) showed single dose cures in malaria clinical trials​ → Our cryptosporidiosis late lead progressed towards candidate selection​ → The hit to lead malaria target based projects have identified new potent drug-like leads

Annual Report

Hits →

Hit to lead →

Malaria – M5715 Cryptosporidiosis – KRS Malaria – Pf KRS Malaria – Pf AcCS Malaria – Pf KRS BU Multiple target-based series

Collaborators and funders:

Lead optimisation →

Pre-Clinical →

Clinical →

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Drug Discovery Unit

Tuberculosis portfolio We identify new drug candidates for tuberculosis (TB) that should significantly reduce the current six months duration of treatment. TB is normally the leading cause of death by an infectious agent worldwide (only displaced recently by COVID-19). Some 10 million people are infected each year, and an estimated 1.5 million people died from TB in 2020. Evidence is emerging that COVID-19 has set back years of progress on combatting TB, due to reduced access to healthcare facilities since the pandemic began. Multi- and extensivelydrug resistant strains of TB continue to arise, so there is an urgent need to discover new drugs to overcome increasing resistance to front line therapies. As a member of the Tuberculosis Drug Accelerator (TBDA) and European regime accelerator for new TB treatments (ERA4TB) we work with numerous academic and Pharma partners across the globe to achieve our goals.

→ Target based projects focussing on high value, novel mechanisms of action, targets → Working with the NIAID to determine the rate and routes of compound metabolism by TB using a high throughput in vitro method

Key highlights for 2021​ → Our compound PS1 achieved best recorded efficacy in our collaborator’s chronic model of TB

Portfolio overview

→ Our profiling of preclinical candidate KS1 demonstrated promising efficacy in chronic models of TB and in combination with other TB drugs

Our work on TB ranges from early hit discovery to preclinical candidate selection. Our main areas of activity are:

→ We identified several series from phenotypic screening and found one suitable to enter lead optimisation

→ Phenotypic screening of compound libraries against TB grown in culture (more than one million compounds screed to date) through collaboration with NIAID (Prof Clifton Barry)

→ We established a screen for a new TB target

Hits →

Hit to lead →

Target-based KS1 Phenotypic series 1 Phenotypic series 2 Multiple phenotypic series Novel targets

Collaborators and funders:

Lead optimisation →

Pre-Clinical →

Clinical →

Annual Report

Coronavirus portfolio The Coronavirus portfolio was started in June 2020 to identify novel therapies for the treatment of COVID-19 and other potential pandemic coronaviruses. The on-going Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) outbreak has resulted in excess of 400 million infections and 5 million deaths. Despite the success of the vaccination programmes, the emergence of new variants and care for those unable to be vaccinated highlights the significant need for novel small molecule therapeutics to treat the disease.

The DDU is an associate member of the IMI CARE consortium which aims to deliver treatments for the current and future coronavirus outbreaks.

We are committing all hit chemical matter to the consortium and now have active hit to lead programs against both targets.

We are an Associated Partner In CARE, an Important title as it positions us alongside the Pharma partners.

Early in the pandemic, the DDU, working with Principal Investigators in the School of Life Sciences, developed and ran two high throughput screens against key antiviral targets. In collaboration with Professor Victoria Cowling and leveraging existing discovery expertise in methyltransferases we rapidly developed a novel viral methyltransferase assay and screened a repurposing library against this exciting discovery target – the importance and impact of this work was highlighted when it was featured on the cover of SLAS discovery.

Further screening and subsequent development of a hit series has now yielded the first known co-crystal structure of this target with a bound inhibitor – this has the potential to accelerate drug discovery against this target.

Hits → NSP14 NSP3

Collaborators and funders:

Hit to lead →

Lead optimisation →

Pre-Clinical →

Clinical →

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Drug Discovery Unit

Innovative Targets portfolio Most academic research into disease biology is insufficiently validated for direct incorporation into pharmaceutical company pipelines. Consequently, an enormous amount of scientific research in UK universities fails be translated into public health benefit. Our innovative targets portfolio seeks to translate academic research and novel drug targets into licensable data packages suitable to attract follow-on investment.

ITP sources innovative biology from leading investigators across the UK and beyond and forms active research collaborations and translational plans to validate novel targets with small molecule drug discovery. Data packages including novel chemical

GSK Pfizer Takeda Bukwang AstraZeneca

assets showing proof of concept in cell or tissue models are partnered with the BioPharma industry for onward development.

Translation of research excellence into tangible public benefit is at the heart of the University strategy and is evidenced by the impact from the ITP. We continue to deliver a strong pipeline of commercialisation opportunities and sustainable partnerships with industry.

Given the nature of innovative target drug discovery, this group within the DDU is exposed to many different types of disease biology and collaborations with both academia and industry. 2021 provided a balance of

Pharma partnerships

Support for grant applications

Life Sciences Innovation District Newco

ITP Support for grant applications

Academic research

Licence Reagents, assays, chemical tools

Financial return University of Dundee

IOmet Pharma Pacylex Inc Corbin Tx HepaRegenix Ubiquigent In4Derm

Annual Report

industry partnerships – with Takeda, Bukwang Pharma and Beactica Therapeutics, each with aligned academic collaborations in Cambridge, Oxford and Dundee, respectively– and earlier stage target validation projects with investigators in the Universities of Dundee, Oxford and Queen Mary University London.

Another ongoing focus is our participation in the UK Spine, a collaboration with the Universities of Oxford and Birmingham, the Sir Francis Crick Institute, and the Medicines Discovery Catapult. This collaboration aims to improve health in old age by accelerating the development of new therapeutics that overcome the generic processes driving ageing and age-related morbidities.

Hits →

Hit to lead →

Tauopathies RNACapRx Parkinsons disease WRN helicase Ageing

Collaborators and funders:

Another highlight for the ITP was announced in 2021

by HepaRegeniX GmbH; the initiation of first-in-human studies with its lead compound HRX-0215 for liver regeneration. Whilst HRX-0215 is not a DDU compound, the company was established in 2017 following our collaboration with Dr Wolfgang Albrecht, the company’s co-founder and current Managing Director to develop novel inhibitors against a novel proprietary molecular target Mitogen-Activated Protein (MAP) Kinase Kinase 4 (MKK4).

Lead optimisation →

Pre-Clinical →

Clinical →

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Drug Discovery Unit

Spotlight on our Molecular Interaction Team (MIT) Drug molecular mode of action With the increased occurrence of drug resistance in many organisms, the search for more efficient and cost-effective drugs becomes increasingly complex.

Drugs need to selectively target pathogen pathways and inhibit crucial steps with high efficiency while being non-toxic to the human host. While classical strategies of chemical library screening are important, understanding the drugs mechanism of inhibition and its dynamics at a molecular level are now essential.

The lack of understanding of biological targets, which undergo conformations to carry their function, as well as the molecular effect of a drug event often impair abilities to develop efficient therapeutic treatment.

Bioinformatics and homology modeling

BIO

M I S T RY AM

Cloning and expression

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The Molecular Interaction Team was created in October 2020. It is composed of 17 experts in protein expression, crystallisation and biophysical techniques with Dr Vincent Postis joining in May 2021 as team leader. Its aim is to develop the pipeline from molecular cloning, expression, purification and biophysical characterisation of target proteins up to structure determination. By streamlining the pipeline and working closely with other teams (cell biology, biochemistry, and computational chemists) and all of the drug discovery portfolios, the MIT has a central role in the DDU for drug discovery. Altogether its missions are to structurally enable projects, biophysically characterize interactions, characterize new targets and actively support DDU priorities.

Biochem assays

Protein production

Targets Refinement and optimisation

Cellular assays

Biophysical studies

Dissemination of data

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Structure determination

I S T RY T

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Model validation

EM

Compounds

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Annual Report

For this reason, the team is focusing on drug-target interaction biophysical characterisation. Besides the already available crystallography, NMR and SPR platforms, the MIT is developing parallel cutting-edge approaches such as cryoEM and fluorescence-based assays. These will allow a fast-track characterisation at a molecular level of drug-target interactions. The enhanced understanding of the intricacies of these molecular interactions will empower computational chemists to design more efficient drugs, with powerful impacts on drug discovery.

Structure based drug design in the AlphaFold era The optimisation of target biophysical characterisation coincides in a timely manner with the development of AlphaFold by DeepMind and Rosetta by the Baker group which can predict protein folding and structure.

The MIT team will take full advantage of these artificial Intelligence (AI) driven systems in interpreting its biophysical characterisations of small moleculeprotein interactions.

Ambitions for the MIT The focus of the Molecular Interaction Team is to embrace new biophysical and AI technology to improve and accelerate the drug discovery process. To this extend, the team is structured in subdisciplines led by expert scientists coordinating the research support for our drug discovery portfolio teams. The MIT will enhance the DDU’s potential to streamline the delivery of fully characterized drug candidates.

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Governance and structure DDU structure The DDU Senior Leadership Team brings extensive industry experience to the Unit and has secured over £100M in translational funding since it was established in 2006.

We share a drive and determination to improve the translation of academic research by working on novel, often unprecedented, targets and applying industry-standard processes and decision making. This has helped to make the DDU a partner of choice for pharma, funders and academic partners alike.

Our extended leadership team has been selected from our portfolio and discipline leaders and are working closely with SLT at a strategic level.

Head of DDU and Director of WCAIR Paul Wyatt

Senior Leadership Team Head of Chemistry

Head of DMPK

Head of Biology

Head of Parasitology

Head of Business Development

WCAIR Manager

Finance Business Partner

Ian Gilbert

Kevin Read

David Gray

Manu de Ryker

Julie Brady

Catharine Goddard

Louise Burns

Extended Leadership Team Laura Cleghorn

Beatriz Baragana

Fraser Cunningham

Vincent Postis

Fabio Zuccotto

Gary Tarver

TB Portfolio Lead

Apicomplexan Portfolio Lead

COVID Portfolio Lead

Head of Molecular Interaction

Head of CompChem

Synthetic Methodologies Team Leader

Annual Report Beatriz Baragaña Beatriz joined the Drug Discovery Unit in 2010, as a medicinal chemist became Portfolio Lead for the Apicomplexan Portfolio in 2016. She has played a key role the discovery of DDD0107498 a drug candidate for the treatment and prevention of malaria currently undergoing clinical trials and her team has received twice the Project of Year award from Medicines of Malaria Venture (MMV) in 2014 and 2018.

Beatriz gained her PhD in Organic Chemistry from the University of Oviedo (Spain) under the supervision of Prof. Barluenga and went on to join Professor A. P. Davies’ lab at Trinity College (Dublin). She them moved to industry as a postdoctoral Medicinal Chemist at Bayer AG (Wuppertal, Germany). In 2001, she joined Avecia (now Piramal Pharma) where she became a team leader working in antibody drug conjugates for the treatment of cancer.

Laura Cleghorn Laura joined the DDU at the point of its inception in 2006, initially working as a medicinal chemist working on Human African Trypanosomiasis before changing focus to TB in 2013, becoming Portfolio Leader in 2019. Laura obtained her BSc (Hons) in Chemistry from the University of Edinburgh in 2001, following this she became a medicinal chemist working at Organon Laboratories before moving to the University of Leeds to complete a PhD in chemistry. Laura leads a team of scientists internally and as a part of external consortia to discover new series that inhibit TB and develop them towards preclinical drug candidates against TB.

Fraser Cunningham Fraser joined the DDU in October 2019 to co-lead the medicinal chemistry team in the innovative targets portfolio. He has provided chemistry and strategic leadership in ITPs industry collaborations with Takeda and Bukwang before becoming Coronavirus Portfolio Leader in 2021. Prior to joining the DDU Fraser was a post-doctoral researcher with GSK working in both their Diseases of the Developing World and Immuno-inflammation units where he gained experience in both phenotypic and target-based drug discovery.

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Drug Discovery Unit Vincent Postis Vincent joined the DDU in May 2021 as the Molecular Interaction Team Leader. Vincent is a structural biochemist specialised in highthroughput strategies and biophysical techniques. With a strong track in membrane proteins studies, detergent free methods and antimicrobial resistance, he brings a specialised expertise to Drug Discovery Unit.

Gary Tarver Gary joined the DDU in January 2018 and is currently Synthetic Methodologies Team Leader. The team is responsible for development of new synthetic methodology, flow chemistry, chemical route development, optimisation, scale up and chemistry automation. Prior to joining the DDU Gary worked as a medicinal chemist at Organon, chemistry scale up team leader at Schering-Plough and Merck and lead chemist developing new automation technologies at Cyclofluidic and NewPath Molecular.

Fabio Zuccotto Fabio is a highly experienced Computational Chemist having worked in pre-clinical drug discovery for nearly 25 years across a broad range of therapeutic areas and target classes. He joined the DDU in 2013 becoming Head of Computational Chemistry in June 2021 leading a team of 10 scientists focused on delivering Molecular Modelling, Machine Learning and AI solutions to drug discovery projects. In his previous role he was leading the Fragment Based Drug Discovery team at Nerviano Medical Sciences (Milan, Italy) where he contributed to the development of three clinical candidates. Prior to this Fabio has held Computational Chemistry roles in several Industrial and Academic organisations (Inpharmatica, London – UK, GlaxoWellCome, Stevenage – UK, Leicester University Centre for Mechanism of Human Toxicology – UK) gaining a broad experience in in silico methodologies.

Fabio graduated with a Bsc/Msc degree in Chemistry from University of Milan (Italy) and a PhD in Computational Medicinal Chemistry from the University of Cardiff (UK). He is a co-author on over 50 publications and patents.

Annual Report

Advisory Boards and Committees Each of our portfolios reports to a Scientific Advisory Committee consisting of representatives from the pharmaceutical industry as well as our funders.

WCAIR SAC

Kinetoplastid Portfolio SAC

WCAIR SAC includes expert advisers in the fields of drug metabolism and pharmacokinetics, medicinal chemistry, anti-infectives drug discovery, toxicology and clinical trials. This international group meets once per year in Dundee (travel permitting) and once remotely. The SAC has a consultative function, advising both the host institute (UoD) and funder (Wellcome).

The kinetoplastid SAC function is to analyse and provide advice regarding drug targets, prioritisation and progression of projects, and development of lead series. It comprises independent advisers with expertise in the fields of drug discovery, medicinal chemistry, anti-microbial therapy and clinical trials in addition to representatives of Wellcome. This SAC meets twice annually.

→ Graeme Bilbe (Chair), Senior Advisor, formerly Chief Scientific Officer, Research and Development Director DNDi → Mike Blackman, Professor of Molecular Parasitology, Francis Crick Institute → Simon Croft, Professor of Parasitology, London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases → John Kelly, Professor of Molecular Biology, Department of Infection Biology, London School of Hygiene and Tropical Medicine → Paul Leeson, Director, Paul Leeson Consulting Ltd → Julian Rayner, Professor of Cell Biology, Cambridge Institute for Medical Research and Dept. Clinical biochemistry, University of Cambridge → Steve Rees, Vice-President Discovery Biology at AstraZeneca. → Isabela Ribeiro, Head, Dynamic Portfolio Unit, DNDi

→ Graeme Bilbe (Chair), Senior Advisor, formerly Chief Scientific Officer, Research and Development Director DNDi → Argyrides (Archie) Argyrou, Associate Principal Scientist, AstraZeneca, Cambridge, UK. → Jeremy Burrows, VP, Head of Discovery, MMV → Simon Croft, Professor of Parasitology, London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases → Laurent Fraisse, Research and Development Director, DNDi → John Kelly, Professor of Molecular Biology, Department of Infection Biology, London School of Hygiene and Tropical Medicine → Paul Leeson, Director, Paul Leeson Consulting Ltd → Karine Malagu, Group Leader, Medicinal Chemistry, Charles River, U.K. → Isabela Ribeiro, Head, Dynamic Portfolio Unit, DNDi

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ITP SAB

Chemistry Advisory Board

Our ITP SAB support the selection and progression of innovative target proposals and projects. It comprises a number of highly regarded internal and external drug discovery experts. The SAB is chaired by Prof Paul Wyatt and meets twice a year, with applications needing a quicker response being reviewed electronically in the interim.

We have also established a cross-DDU Chemistry Advisory Board to assist with our translational research by advising on chemistry methodologies and strategies.

This group of experts provides more direct support to our chemistry teams and portfolio leaders across the DDU to identify optimal ways of delivering research objectives and assessing innovative methodologies and approaches.

→ Paul Wyatt (Chair), Professor of Drug Discovery, Baxter Chair of Chemistry and Head of the Drug Discovery Unit → David Gray, Head of Biology and Professor of Translational Biology, DDU → Mike Ferguson, Regius Professor of Life Sciences, University of Dundee → Mike Ashford, Professor of Neuroscience, University of Dundee → Robin Carr, Director Home Farm Bioscience Consulting → Heather Giles, CEO, Chief Scientific Officer Vapogenix Inc. → Neil Thompson, independent consultant → Paul Leeson, Director, Paul Leeson Consulting Ltd Tuberculosis SAC The Tuberculosis SAC meets annually and comprises expert advisers from the field including representatives from the Gates Foundation and TBDA. The purpose of the SAC is to advise and analyse the progression of hit and lead series. → Peter Warner, Senior Program Officer, Bill and Melinda Gates Foundation → Valerie Mizrahi, Director, Institute of Infectious Disease and Molecular Medicine → Nader Fotouhi, Chief Scientific Officer, TB Alliance → Anna Upton, Senior Vice President, Head of Tuberculosis Research and Development, Evotec → Robert Bates, Director, Head of TB Discovery, GSK → Paul Smith, Pharma Consultant → Steve Berthel, TBDA Medicinal Chemistry Lead and Program Manager

→ Professor Varinder Aggarwal, Professor in Synthetic Chemistry, University of Bristol → Professor Tim Cernak, Assistant Professor of Medicinal Chemistry and Chemistry, University of Michigan → Dr David Lathbury, Astute Chemical Development Consulting Ltd → Dr Paul Leeson, Director at Paul Leeson Consulting Ltd → Professor Adam Nelson, Professor of Chemical Biology, University of Leeds → Dr Steve Taylor, Founding Director at Celbius Ltd UoD Advisory Group The University has established an advisory group consisting of senior representation from the University Executive Group and School of Life Sciences Leadership Group. Meeting tri-annually to maintain connectivity between the DDU and University at a strategy level. → Professor John Rowan, Vice-Principal (Research, Knowledge Exchange and Wider Impact) → Prof Julian Blow, Dean of the School of Life Sciences → Ms Carol Prokopyszyn, Director of Finance → Dr David McBeth, Director of Research and Innovation Services → Mr Owen Adams, School Manager, School of Life Sciences

Annual Report

Career development The DDU strategy relies on our people. Our 130 staff come from a diverse background both in terms of prior experience and geographical origins. We are committed to ensuring that the DDU is an enjoyable, rewarding and challenging place to work and offers opportunity for career progression.

Keeping our people connected as physical access to the university premises was restricted was a primary objective with routine “virtual coffee breaks” and team meetings supplemented with quiz nights and other social activities.

As part of the DDU’s ongoing commitment to members personal and professional development the Senior Leadership Team has established a Training Matrix to support the development of our next generations of leaders. The Training Matrix identifies key general skills required at each grade and provides a framework for discussions between line mangers and team members to set individual learning objectives for current and potential future roles. Cohorts of next generation team and discipline leaders have also been identified for leadership development. We have identified external trainers to supplement on the job training and university run professional development courses.

These individuals will be presented with portfolio, discipline-based and line management advancement opportunities. Training is also an important aspect of succession planning within the DDU. Looking towards the next 5-years our focus is on succession planning and the alignment of our next generation of leaders. Our Portfolio and discipline leads have been brought together to form an Extended Leadership Team. These individuals, who already have significant leadership responsibility and experience are going through rigorous external leadership training in support of their current roles and also to develop them to the level where they could be considered for opportunities arising to add to or replace members of the current DDU Senior Leadership Team.

Overall, we commit to recognising and rewarding good work and behaviours at a team and individual level.

Recruitment and retention The DDU is widely recognised as the most developed and complete drug discovery engine working across multiple therapeutic areas in UK academia. One of the DDU’s core strengths is our people and the ability to draw on a wide range of skills under one roof.

Our expertise from across the biopharmaceutical industry and academia, combined with outstanding facilities, has created a unique position for industryready drug discovery within a powerful academic environment. Our scientists are passionate about making a difference to the lives of patients and are particularly motived to deliver new therapeutics to diseases impacting low-and middle-income countries where unmet need is highest.As part of the University of Dundee we offer attractive employment conditions including the University Superannuation Scheme and flexible working policies.

The diversity of our staff (and students) helps to make the University of Dundee a UK university of choice for undergraduate, postgraduate and distance learning.

Family friendly policies, staff networks for BAME, Disabled and LGBTQ+ staff, membership of Athena SWAN, the ECU Race Equality Charter and Stonewall as well a full range of disability services, create an enjoyable and inclusive place to work.

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Finance The DDU receives funding and support from charities, research councils, industry, private foundations and the University of Dundee. These monies are largely project specific and are managed in line with university charitable financial regulations.

The monies awarded to the DDU are inherently variable year-on-year due to the cycles of our research funding.

Many awards are for 3 – 5 year programmes of activity, such as the Wellcome Centre for Anti-Infectives Research and Kinetoplastid Portfolio Award both of which were recognised in 2017. Renewal of these awards will be recognised in 2022.

2021 was a successful year for the DDU with 10 new awards including support from Wellcome allowing us to initiate new research into schistosomiasis, collaboration

funding to develop a new Global Health Diversity Library with the Bill & Melinda Gates Foundation and sponsored research programmes with industry for projects in neurodegeneration and oncology.

Annual income by the DDU demonstrates a managed growth over the period 2015 – 2021. This reflects an increased headcount from 70 to 124 directly funded scientists over the period as well as an increased cost of goods.

Research Councils and charities, including the Wellcome Trust, continue to contribute circa 50% of the DDU annual income, with further significant support from private foundations such as the Bill & Melinda Gates Foundation.

Drug Discovery Unit funder types

University of Dundee Charities Research Councils Industry Private Foundations

Annual Report

Monies awarded to Drug Discovery Unit £ Millions 30 25 20 15 10 5 – 2015

2016

2017

2018

2019

2020

2021

2017

2018

2019

2020

2021

Annual Drug Discovery Unit income £ Millions 14 12 10 8 6 4 2 – 2015

2016

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Drug Discovery Unit

Closing remarks As the outgoing Head of the DDU, I now (almost) have the time to reflect back on the truly amazing journey we have been through over the past almost 16 years.

No one imagined how the DDU would develop from the empty labs when I first visited Dundee back in 2006, to the fully functional, professional drug discovery organisation of 130 people as of today. The main part of our annual report outlines the major advances we have made across many fronts, even just this past year, but it has been a highlight to have delivered four compounds for clinical development and helped to create a number of new companies. I have my fingers crossed for further additions in preclinical development in the near future.

The DDU team has expanded and evolved over time and everyone has played a part in our development and successes, so thank you to all past and present DDU members for the making it possible, and your hard work and commitment. It has been highly rewarding to watch many of you grow and blossom over the years, and for some of you to take up senior positions within the DDU. Although, it’s difficult to single out individuals, I would like to thank Mike Ferguson and Alan Fairlamb for conceiving the concept of DDU and giving me the opportunity to take on the leading role in its journey and particularly to Mike for his mentorship and friendship that has guided and sustained me. I would also like to thank the DDU Senior Management Team (David Gray, Kevin Read, Louise Burns, Manu De Rycker, Ian Gilbert, Julie Brady, Catherine Goddard) for your support, massive contributions, and keeping me sane and driving me insane over the years.

A further key element of the DDU is that everything we do is in collaboration. This has not only helped us deliver our programmes and improved our approaches to drug discovery but also has given me the opportunity to develop many wonderful collaborations and make friends, too many to list here, and to visit some amazing places. Although I will not miss the hours sitting in airports, I will miss working and socialising with you, so thank you for your help with our programmes and your camaraderie.

Finally we could not have developed and sustained the DDU without backing from the University of Dundee and our funders, so thank you all for your generous support.

I would particularly like to thank Diana Tay and Peter Warner for your help and guidance over many years. I will miss filling out your grant application forms and the thrill of receiving news of successful applications. It has been like winning the lottery many times over, without having a flash car to show for it.

My departure is far from the end of the DDU. As everyone is now horribly aware, there are many challenges in the future from infectious diseases old and new, particularly ones not noticed because they don’t directly affect G20 countries (yet) and other diseases that pose a constant and growing threat to all, neurodegeneration, cancer, antibiotic resistance. The DDU remains highly committed to playing its part in addressing these threats and has an excellent team and facilities to deliver many more achievements in the future whatever the disease. So best of luck, success and health to all the team for the future.

Annual Report

Finally, as Director for the Wellcome Centre for AntiInfectives Research (WCAIR), I would like to acknowledge the major impact the Centre activities have had on advancing the DDU’s drug discovery approaches and technologies. The WCAIR’s output has been outstanding, thank you all for your hard work and dedication.

While being Head of the DDU has been challenging, and sometimes tough and frustrating, these downsides have been swamped by the opportunity to develop something very rare and precious, that can contribute to saving and improving many lives in the future and make many great friends across the world. I would commend the role of Head of the DDU to anyone who wants to make a difference to the world and themselves. So, I will finish by wishing my successor every success and happiness in the role, it will challenge you, but the rewards are more than worth it.

Professor Paul Wyatt (for the time being) Head of the DDU and Director of the Wellcome Centre for Anti-Infectives Research University of Dundee.

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Drug Discovery Unit School of Life Sciences University of Dundee Dow Street Dundee DD1 5EH

ContactDDU@Dundee.ac.uk ddu_dundee drug-discovery-unit-university-of-dundee drugdiscovery.dundee.ac.uk

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