Nucleotide Prodrugs as Treatment for Acute Myeloid Leukaemia

Details

Supervisors: Dr. Youcef Mehellou, Prof. Alex Tonks and Dr. Neil Rodrigues.

Acute Myeloid Leukaemia (AML) is an aggressive and highly heterogeneous haematological malignancy characterised by the uncontrolled expansion of clonal myeloid precursor cells within the bone marrow. This abnormal proliferation suppresses normal haematopoiesis, leading to life‑threatening complications. In the UK, AML accounts for roughly 3,100 new diagnoses each year, with a median age at diagnosis of approximately 68 years. Although treatment strategies have evolved in recent years, particularly with the advent of targeted therapies for genetically defined subgroups, overall mortality remains high, with around 2,700 deaths annually. A major contributor to this high mortality rate is the frequent emergence of resistance to frontline chemotherapeutic agents and targeted therapies. Consequently, there is a critical need to develop novel therapeutic approaches capable of overcoming resistance mechanisms and improving clinical outcomes.

This PhD project aims to address this unmet medical need by leveraging advanced phosphate‑based prodrug technologies to enhance the pharmacological properties of therapeutic nucleotides. Nucleotides and their analogues have long been recognised for their potential as anticancer agents; however, their clinical utility is often limited by poor cellular uptake, rapid degradation, and unfavourable pharmacokinetic profiles. Prodrug strategies, where molecular modifications are used to improve a compound’s bioavailability, metabolic stability, or cellular delivery, represent a powerful means of overcoming these limitations.

Building on our research group’s extensive expertise in prodrug‑based drug discovery, this project will focus on designing and synthesising a novel series of nucleotide prodrugs tailored to circumvent resistance pathways encountered in AML. The successful candidate will explore multiple prodrug motifs, thereby enhancing membrane permeability and enabling efficient intracellular activation.

The experimental work will involve:

·      Rational drug design, informed by structure–activity relationships and known resistance mechanisms.

·      Chemical synthesis of nucleotide prodrugs using modern synthetic organic chemistry methodologies.

·      Purification and analytical characterisation, including NMR, LCMS, and chromatographic techniques.

·      Serum stability and metabolism assessments to evaluate prodrug activation pathways.

·      Biological evaluation of synthesised compounds using a panel of AML cell lines, assessing cytotoxicity, intracellular nucleotide release, and potential to bypass known drug resistance mechanisms.

Throughout the project, the PhD student will gain comprehensive, interdisciplinary training that spans medicinal chemistry, chemical biology, and cancer pharmacology. They will acquire hands‑on expertise in small‑molecule design, multi‑step synthesis, analytical method development, and in vitro biological assay development. Such broad training will equip the student with a highly competitive skill set suitable for careers in academic research, the pharmaceutical industry, or the biotechnology sector.

The student will work within an active research group with strong collaborative links, ensuring excellent mentorship and opportunities for professional and scientific development.

Contact Dr. Youcef Mehellou (MehellouY1@cardiff.ac.uk) for informal inquiries.

You can apply online – consideration is automatic on applying for a PhD with an July/October 2026 start date.

Please use our online application service at: https://www.cardiff.ac.uk/study/postgraduate/research/programmes/programme/pharmacy