This project aims to take important steps towards developing a drug that will target the Achilles' heel of the cancerous cells found in 1 in 5 patients diagnosed with high grade serous ovarian cancer. Patients with this form of cancer currently have a very poor prognosis, and undergo harsh chemotherapy that provides limited benefits in terms of quality or duration of life. The vulnerability of the ovarian cancer in these patients arises from the fact that these particular cancer cells have multiple copies of the gene that encodes cyclin E. This results in cyclin E protein being produced at abnormally high levels and as a consequence the cells become addicted to cyclin E for their ability to further divide and survive. Our structural studies have provided novel insights into how aberrant cyclin E signaling may be prevented with a small molecule inhibitor, which would be selectively toxic to ovarian cancers that are dependent upon this pathway for survival. The project team has extensive expertise in drug discovery and has established the experimental systems needed to develop such inhibitors, with chemical start points being identified. The team has also formed collaborations with clinical experts who specialise in the treatment of aggressive ovarian cancers. Clinicians would be able to easily identify the patients with elevated cyclin E who would benefit from a drug developed for these tumour cells; an example of a personalised medicine. By the end of the project, the team aims to have developed the inhibitors to a point where they can demonstrate selective effects on ovarian cancer cells with elevated cyclin E levels. This would position the project for further development involving the final optimisation of inhibitors towards a drug that could be developed for clinical use.

Rational computational design plays an increasingly important role in today's society, and is widely used in, for example, the construction and automotive industries to reduce costs associated with conventional experiments. If we are to apply the same principles to the design of pharmaceutical molecules, then it is necessary to be able to predict with high accuracy which of the multitude of molecules that we can potentially synthesise in the lab actually have therapeutic benefits. Ideally, the computer program would be able to perform this function using only established laws of physics, rather than relying on data input from experimental measurements. The modelling of atoms at this fundamental level is known as first principles simulation. First principles simulations are used today by researchers in many industries, including microelectronics and renewable energy, to rapidly scan multitudes of hypothetical material compositions. Only once a set of materials matching the desired properties is discovered, does the costly process of manufacturing those materials in the lab begin. So why are the same first principles techniques not used to design new pharmaceutical molecules? The equations of quantum mechanics were written down and shown to describe the atomic-scale behaviour of materials with remarkable accuracy as early as the beginning of the twentieth century. Therefore, the answer is not a lack of physical understanding. Instead, it is largely a problem of the computational effort required to model the large numbers of atoms that are involved in interactions between a pharmaceutical molecule and its therapeutic target. There are an unimaginable number of silicon atoms in typical modern electronic devices, but importantly the homogeneity of the structures means that the bulk material can be represented by just two atoms periodically repeated in 3D, and it is a relatively straightforward problem to computationally model the properties of this simple system. In contrast, biological systems are much more complex and often we need to simulate many thousands of atoms in order to accurately predict the relationships between the molecule's structure and its function. However, due to increases in computer power and, more importantly, fundamental advances in software design, first principles approaches can now access these biological systems with precisely the same accuracy that is used to study silicon. Traditional approaches to computational drug discovery rely heavily on hundreds of model parameters that have been collected over many decades from experiments or computational analysis of small molecules. My idea is to dispense with these parameters and instead compute them directly from first principles quantum mechanical simulations of the biological therapeutic target, such as a protein that is implicated in disease. These new model parameters, rather than being generic, will be specific to the system under study and will thereby transform the accuracy of computational biomolecular modelling. The improved computational models will be used to scan hundreds of potential pharmaceutical molecules for therapeutic benefit, thus allowing us to rationally and rapidly design new therapeutic candidates. Medical researchers will be able to focus their design efforts on synthesising only the most promising molecules, thereby improving the likelihood of success in the early stages of pharmaceutical development and decreasing the cost of medicines to the patient. This concept will be put into practice in collaboration with the Northern Institute for Cancer Research at Newcastle University for the design of novel cancer therapies.

Catalytic multicomponent reactions that transform the C=C bonds of alkene feedstocks into complex molecules for the interrogation of biological systems are a cornerstone of modern synthesis. The intrinsic multifaceted reactivity of C=C bonds can be unlocked by many catalytic activation modes. When combined with the structural & functional diversity inherent to the ubiquitous classes of alkene feedstock, these activation modes offer remarkable flexibility for programmable synthesis of complex architectures.1 Among many classes of these reactions, transformations that form new C-C & C-N bonds are an attractive starting point for new methodologies involving transition metal-catalyzed aminoarylation. Recently, we reported a distinct catalysis platform that enables a multicomponent coupling of alkenes, aryl-electrophiles & NaN3, providing single-step access to synthetically versatile & functionally diverse beta-arylethylamine derivatives. Driven by visible-light, two discrete Cu-catalysts orchestrate Ar-radical formation & azido-group transfer steps, which underpin an alkene azido-arylation (AAA) process. The reaction exhibits broad scope in alkene & Ar-components & the azide-anion performs a multifaceted role as both nitrogen source & in mediating the redox-neutral dual-catalysis platform via inner-sphere electron transfer. The synthetic capabilities of this anion-mediated AAA & development of its related reactions is likely to be of utility in a variety of pharmaceutically relevant & wider synthetic applications. Despite several notable advances, the vast majority of synthetic chemistry is conducted in 'one-at-a-time' batch fashion using equipment that has not, essentially, changed since urea was first synthesized by Wöhler in 1828. Most synthetic chemistry is still based on a work flow that often involves routine operations and is labour-intensive & time consuming. Over the last four years, the PI & team have established a ns-HTE platform, such that we can execute & analyse 1000s of parallel & discretely programmable reactions across a wide range of chemical reaction space. The platform is facilitated by liquid handling robots (LHRs), which enables reactions to be set up on a micro or nanomolar scale. To analyse reaction mixtures from 384 or 1536-well plates, we can choose from quantitative & semi-quantitative LC-MS, high-throughput (HT) qNMR & parallel HT-TLC. Together these techniques allow unparalleled quantification & structure determination of products on a short timescale. Together we aim to use HTE to epxlore a new type a catalysis for the synthesis of complex molecules from alkenes. The 'anion-gated dual catalysis' platform brings together three readily available building blocks in a process controlled, ultimately, by a simple anion. The products can be advnaced to functional molecules that have unexplored properties in biologial systems, providing a means to explore new chemical and biology space.

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.

Humanity faces critical global challenges in supplying clean energy, food, medicines and materials for a population forecast to reach 10 billion by 2050. Chemical synthesis will play a central role in addressing these challenges, as organic molecules are the fundamental building blocks of drugs, agrochemicals, and materials. However, the synthesis of most chemicals remains energy intensive, requiring fossil fuel feedstocks and endangered metal catalysts, and produces huge levels of waste - far from what is needed for a net-zero future. The essential transition to a circular chemistry economy will materialise only with a total re-think of organic synthesis: a 'Chemical Revolution' is urgently needed, for which Industry users will require a 'next generation' of suitably trained graduates. Without such change, the chemical industry will not be able to sustain the necessary pace of innovation in new chemical technologies, in the face of rapidly changing chemical regulation and policy, thus rendering this CDT crucial for the future of UK PLC. The Oxford-York ESPRC CDT in Chemical Synthesis for a Healthy Planet will deliver world-leading, ground-breaking training to a next generation of synthetic chemists, developing a sustainable, innovative chemistry culture that equips them to address major emerging and future global challenges in Human Health, Energy and Materials, and Food Security. In doing so, we meet a critical User Need, by supplying the workforce that is essential to create the innovative solutions UK chemical industries urgently require. Our overarching objective is to train students to supersede current practices for the synthesis of functional organic molecules by developing sustainable, field-advancing synthetic pathways to the complex targets needed in drug discovery, agrochemistry, and materials development. Our student cohorts will work together in a training period at both Oxford and York, before engaging with industry co-supervised projects in four research fields that develop innovative, sustainable transformations and synthetic strategies, and apply them in pharma, agro and materials chemistry contexts. With around a third of projects supervised jointly at Oxford and York, we will ensure a strong cross-institute connection; whole programme meetings and research field seminars will enable students across multiple cohorts to contribute to and elevate each others' science. Our association with the Eur1.25bn Center for the Transformation of Chemistry brings a unique connection for our students to a major initiative that is aiming to revolutionise chemical synthesis, as well its >140 chemical organisations across Europe. Our partnership with >10 SMEs and their Entrepreneurs-in-Residence will develop entrepreneurial skills and ensure students are exposed to the cutting-edge of chemical innovation in UK PLC. The applications and benefits from the CSHP CDT are many: Primarily, we will develop a UK-wide network of sustainably-minded, innovative chemists ready to meet the urgent User Needs of the UK chemical industry, bolstering this major sector of UK PLC. The scientists graduating from the CSHP CDT, the high-level science they produce, along with the related tools and technologies, will all contribute to the UK's ambitions as a Physical and Mathematical Sciences Powerhouse. We will set new benchmarks for graduate training by ensuring sustainability is embedded and visible in all research and its outputs, as well as influencing and connecting to graduates across the UK through biennial symposia. Our cohorts' work as Sustainability Ambassadors will permeate our exciting discoveries and the message of the future role of synthetic chemistry throughout society - from school to the general public. Above all, we believe this rigorous and inspirational programme is utterly essential if the UK is to remain globally competitive in the rapidly evolving chemistry landscape.