Structural Chemical Biology of Molecular Glue Degraders Mode of Action

• Funding – self-funded/externally sponsored applicants  (PhD Fees can be found here)
• Applications are accepted year round
• Standard Entry dates – January and September
• Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline.

This PhD project will define how novel molecular glue degraders (MGDs) hijack and reprogram E3 ligases to trigger selective protein ubiquitination and proteasomal degradation. The student will combine structural, biophysical, chemical biology and proteomic approaches to reveal atomic and mechanistic rules that govern glue-mediated engagement, selectivity and downstream fate — and to apply those rules to design tuneable, higher‑performance degraders with translational potential.

Why this is exciting?

Targeted Protein Degradation (TPD) is a rapidly transformative therapeutic modality with major academic and industrial investment (Nat. Rev. Cancer. 2025). Molecular glues — monovalent degraders that stabilise or create protein–protein interfaces — offer routes to drug previously intractable targets. Recent work from the Ciulli Lab has uncovered unconventional glue mechanisms – e.g. intramolecular bivalent glues (Nature 2024), and covalent recruitment of novel E3s, including dual E3 engagement (bioRxiv 2025) that challenge canonical models and open new opportunities for rational design. This project sits at the interface of basic mechanism and translational chemical biology and promises high‑impact mechanistic insight and tool compounds.

Key research questions

• What are the structural architectures and conformational changes induced by MGDs when engaging targets and E3 ligases?
• How do binding thermodynamics/kinetics, intrinsic low‑affinity pre‑existing E3:substrate interactions, and cellular context determine selectivity, ubiquitination sites and degradation outcomes?
• Can structure–mechanism principles be used to rationally tune E3 dependency, potency and resistance profiles (e.g., dual‑E3 or ligase‑switchable degraders; intramolecular bridging, covalent recruitment)?

Approaches and objectives

Structural biology: determine cryo‑EM and X‑ray structures of binary and ternary assemblies of MGDs; use solution NMR to probe dynamics and disordered regions.

• Biophysics: map affinities, kinetics, cooperativity and allostery (SPR, ITC, single‑molecule and ensemble assays) to define thermodynamic/kinetic landscapes.
• Chemical biology & medicinal chemistry: design and test analogue series and “degradation‑tail” variants to dissect chemical determinants of ligase preference and potency.
• Cellular & proteomic interrogation: use engineered cell lines, ubiquitinomics and quantitative MS‑based interactomics to identify target/neo‑interaction sites, ubiquitination patterns, off‑targets and degradation dependencies.
• Functional tuning: exploit chemical perturbations to fine-tune E3 engagement and target/isoform selectivity.

Training and environment

The student will be based in the Ciulli lab at the Centre for Targeted Protein Degradation (CeTPD, https://www.dundee.ac.uk/cetpd). The project can be tailored to the student specific interests and motivations, allowing the student to gain hands‑on training across structural biology (cryo‑EM, crystallography, NMR), biophysics, medicinal chemistry/compound design, chemical biology, CRISPR cell engineering and state‑of‑the‑art MS proteomics. The project is co‑supervised by Professor Ronald Hay, leveraging deep expertise in ubiquitin biology and proteostasis. The Ciulli and Hay laboratories have longstanding collaboration and track-record of co-supervising PhD students leading to high-impact publications (Sci. Adv. 2024). The project will also benefit from access to broad Faculty resources (Drug Discovery Unit, FingerPrint Proteomics Facility) and industry collaborations (e.g., Amphista, Boehringer Ingelheim).

Impact 

This project will deliver mechanistic models and validated chemical tools that define how MGDs operate, establish actionable structure–mechanism guidelines for glue design (including tuneable dual‑E3 strategies), and generate datasets and compounds suitable for high‑impact publications and downstream drug discovery.

References (as cited in text)

Hinterndorfer, M., Spiteri, V.A., Ciulli, A., Winter, G.E. Targeted protein degradation for cancer therapy. Nat. Rev. Cancer. 2025 Jul; 25(7):493-516.

Hsia, O., Hinterndorfer, M., Cowan, A.D., Iso, K., Ishida, T., Sundaramoorthy, R., Nakasone, M.A., Imrichova, H., Schätz, C., Rukavina, A., Husnjak, K., Wegner, M., Correa‑Sáez, A., Craigon, C., Casement, R., Maniaci, C., Testa, A., Kaulich, M., Dikic, I., Winter, G.E., Ciulli, A. Targeted protein degradation via intramolecular bivalent glues. Nature 2024 Mar;627(8002):204-211.

Spiteri, V.A., Segal, D., Correa‑Sáez, A., Iso, K., Casement, R., Muñoz i Ordoño, M., Nakasone, M.A., Sathe, G., Schätz, C., Peters, H.E., Doward, M., Kainacher, L., Cowan, A.D., Ciulli, A., Winter, G.E. Dual E3 ligase recruitment by monovalent degraders enables redundant and tuneable degradation of SMARCA2/4. bioRxiv 2025.08.04.668513; doi: https://doi.org/10.1101/2025.08.04.668513

Crowe, C., Nakasone, M.A., Chandler, S., Craigon, C., Sathe, G., Tatham, M.H., Makukhin, N., Hay, R.T., Ciulli, A. Mechanism of degrader-targeted protein ubiquitinability. Sci Adv. 2024 Oct 11;10(41):eado6492.

Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.