Cardiff University President's Research Scholarship: Drug Discovery: New Clofarabine ProTides as novel Anti-Cancer Agents (PhD Studentship)
Reference Number: R442
Applications will be considered on a rolling basis.
Key Studentship Information
This is a Cardiff University President's Research Scholarship, part of a new £4M investment to coincide with the inauguration of Professor Sir Martin Evans (Nobel Prize for Medicine 2007) as Cardiff’s new President. All of the University Schools and Research Centres offering opportunities under the programme have demonstrated the real potential of the Scholarships to contribute to research excellence through significant, challenging and original PhD research projects and excellent PhD supervision and support.Other attractive features of the Scholarships include the presence of multiple President’s Scholars in each of the research areas and the guaranteed exposure of President’s Scholars to innovative technologies, theories, methodological approaches, and debates.
More information on the President's Research Scholarships scheme is available here: www.cardiff.ac.uk/presidents
Project Title: New Clofarabine ProTides as novel Anti-Cancer Agents
Project Description:
The project description is indicative at this stage and may be subject to change. Please contact Prof Chris McGuigan, mcguigan@cardiff.ac.uk, for further information.
Clofarabine is recently approved agent for acute lymphoblastic leukaemia (ALL) in children and represents the first new agent for childhood leukaemia for over 10 years. It was developed by the Bioenvision Team (Wood / Griffith: external applicants on this award; Wood is a Cardiff MD and Griffith a Cardiff MBA), and included a ca £10M award to Burnett from Cardiff School of Medicine (a co-applicant here) from Bioenvision for its pivotal evaluation in patients.
Clofarbine is a nucleoside analogue related to adenosine but resistant to deamination by adenosine deaminase. As with most nucleoside analogues it functions by active transport into cells followed by kinase-mediated activation to its triphosphate form. Limitations on the efficacy of clofarabine arise from two sources:
(a) A high polarity leading to poor uptake into solid tissue/tumour.
(b) An need for kinase-mediated activation. It is inactive in kinase-deficient cells,such as those slowly replicating. Liphophilic Prodrugs (e.g esters or amides) of clofarabine could address (a), but not (b). The free monophosphate could in theory address (b) but it could not enter cells. We have invented a technology, ‘ProTides’, which can address both.
ProTides function as lipid-soluble pro-drugs of the pre formed free nucleotide. As ProTides contain a 31P atom they are NMR active and detectable by MRI; thus we will liaise with EMRIC to probe cellular and tissue entry by these agents.
Outline of project:
- Computer graphic aided design of new ProTides (Brancale)
- Synthetic organic chemistry to prepare target ProTides (McGuigan)
- Study of their stability in biological media and processing in cells by 31P NMR (McGuigan).
- Study of their localisation in tissue by MRI (Paisey)
- Study of their in vitro action against a range of cancer cell lines (Nicholson)
- Progression to pre-clinical evaluation considering clinical need (Burnett).
Supervisor: Prof C McGuigan, with Dr A Brancale
Proposed Start Date: 1st Ocotber 2012
Funding
This is a Cardiff University President's Research Scholarship. The award includes full UK/EU tuition fees plus a doctoral stipend matching UK Research Council National Minimum (£13,590 p.a. for 2010/11, updated each year).
Number of Awards Available: 1
Eligibility
Academic Criteria: Applicants must have a First Class Honours degree or a 2.1 plus a postgraduate Masters degree (or their equivalents) in a relevant subject.
Residency: Full awards (fees plus maintenance stipend) are open to UK Nationals, and EU students who can satisfy UK residency requirements. To be eligible for the full award, EU Nationals must have been in the UK for at least 3 years prior to the start of the course for which they are seeking funding, including for the purposes of full-time education. EU Nationals who do not meet the above residency requirement are eligible for a fees-only award, provided that they have been ordinarily resident in the EU for at least 3 years prior to the start of their proposed programme of study.
How to Apply
In the first instance, please send a CV and covering letter to mcguigan@cardiff.ac.uk.
Applications will be considered on a rolling basis.
Additional Information:
For more information please contact Prof Chris McGuigan:
TEL: 029 20 874537
EMAIL: mcguigan@cardiff.ac.uk
WEB: http://tinyurl.com/McGuiganLab
ttp://www.cf.ac.uk/phrmy/staffinfo/CMG/Presidentsstudentships.html
