Validation and optimisation of small molecular inhibitors targeting tumour-associated carbonic anhydrase IX: Synthesis of water soluble analogues and prodrugs
Dr S Freeman
Dr R Gieling
Applications accepted all year round
Self-Funded PhD Students Only
Many cancer patients, who have had local and systemic treatment, eventually develop and die from the establishment of distant metastasis associated with relapse in primary tumour growth. Cell populations in hypoxic niches, including cancer stem cells (CSC), that are resistant to conventional chemo- and radiotherapy regimens are important contributors to the loss of control.
Resistant tumour cells and CSCs express high levels of hypoxia-induced carbonic anhydrase IX (CA IX). Targeting CA IX is regarded as a key approach to destroy the resistant cell populations. With the elucidation of the crystal structure of carbonic anhydrase, small molecular inhibitors for CA IX have been developed. We previously found that these CA IX inhibitors based on the sulfamate class are potent and selective inhibitors of cancer cell migration and some “hit compounds” like S4 are very effective preclinical as anti-tumour/metastatic compounds.
CA IX catalyses the hydration (H2O) of carbon dioxide (CO2) to bicarbonate (HCO3-) and protons. Biologically, CA IX plays an active role in tumour physiology principally through its catalytic activity-mediated control of pH and cell adhesion/migration. Hypoxia-inducible factor 1 (HIF-1) signalling is the main driver behind the expression of CA IX. Whilst CA IX helps to retain a relatively neutral pH in tumour cells allowing tumour cells to survive.
This PhD project will involve the validation of CA IX inhibitors to validate the effectiveness in inhibiting tumour growth and aggressiveness in in vitro assays. Lead compound(s) optimisation will include the synthesis of water soluble analogues of S4 and the design and synthesis of prodrugs of S4 to enhance water solubility.
The synthetic chemistry will provide training in several techniques, such as column chromatography, HPLC and NMR spectroscopy. Design of novel molecules may require molecular modelling. Extensive training will also be provided in a variety of cell culture techniques including monolayer and 3D-spheroid cultures, biochemical assays and immunocytochemistry.
This project will be conducted within Manchester Pharmacy School, recently confirmed as the leading UK research base for Pharmacy following the 2014 Research Excellence Framework.
Candidates are expected to hold an MPharm degree or minimum upper-second (or equivalent) degree in a related chemical/biological science or medicinal chemistry. Candidates holding an MSc degree in a related area are particularly encouraged. It is expected that applicants should have some experience of cell culture and biochemical techniques (western blotting, Elisa, FACS) and/or experience in synthesis and characterisation of biological active compounds.
This 3-year full-time PhD is open to candidates able to provide evidence of self-arranged funding/sponsorship. Annual fee rates for this project, due to commence from September 2016 onwards, are:
*UK/EU nationals: £14,000
Non-EU nationals: £27,500
There is potential to start the PhD project in July 2016 if this suits the successful candidate.
Please direct applications in the following format to Dr Sally Freeman (email@example.com):
- Academic CV
- Official academic transcripts
- Contact details for two suitable referees
- A personal statement (750 words maximum) outlining your suitability for the study, what you hope to achieve from the PhD and your research experience to date
- Evidence of funding.
Any enquiries relating to the project and/or suitability should be directed to Dr Freeman. Applications are invited on an on-going basis but early expression of interest is encouraged.
*UK/EU tuition fees are subject to an annual inflationary increase, anticipated to be approximately 2.5% p.a.
Gieling RG, et al. Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts. J Med Chem. 2012 Jun 14;55(11):5591-600
Gieling RG, Williams KJ. Carbonic anhydrase IX as a target for metastatic disease. Bioorg Med Chem. 2013 Mar 15;21(6):1470-6
Jennifer L. Bryant, et al. Inhibiting carbonic anhydrase IX targets hypoxic small cell lung cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4980. Doi:10.1158/1538-7445.AM2014-4980
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