Chronic Myelomonocytic Leukaemia (CMML) is an orphan disease defined by myeloid dysplasia, myeloproliferation and a malignant expansion of classical monocytes. There is no generally effective treatment beyond allogeneic stem cell transplantation, which is an option for only a small minority of patients. For the majority prognosis is dismal, with median survival of 15-20 months following diagnosis.
Chemotherapeutic approaches in CMML (and other leukaemias) frequently fail due to a lack of specificity, or insufficient activity against earlier disease initiating/sustaining progenitor cells protected in the bone marrow niche. We are seeking to address this unmet need by developing a new class of peptide-drug conjugates that mobilize CMML progenitor cells from the bone marrow and selectively kill all CMML cells throughout the disease clone in the bloodstream.
This project will focus on the structure-based design and synthesis of a new class of warheads for inclusion in these peptide-drug conjugates.
This will involve;
1) Medicinal chemistry techniques to design the novel warheads and linkers (i.e. Pymol, property based design).
2) Synthetic organic chemistry techniques to prepare and characterise the warheads.
3) Protein conjugation and characterisation of the conjugates by e.g. SEC, MALDI MS.
4) Biological evaluation using established methods; cell culture, flow cytometry and colorimetric assays.
Through this work we will establish the role of the chemical linker and the physicochemical properties of the warhead in determining the activity and retention of the active species in leukaemia cell lines and patient samples.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with previous laboratory experience are particularly encouraged to apply.
How To Apply
For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/). Informal enquiries may be made directly to the primary supervisor. On the online application form select the appropriate subject title.
For international students, we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences.
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