A team of chemists, cell biologists, and cancer pharmacologists is building cage-like molecules called cryptands to kill drug-resistant cancer cells. Many cancers eventually stop responding to standard chemotherapy drugs, leaving patients with few options. This project tackles that problem head-on by designing synthetic molecular cages that trap metal ions and deliver them directly into tumour cells, bypassing the resistance mechanisms that defeat conventional treatments. The team already has several promising "hit" compounds and will now refine their structure, test them against resistant cancer cell lines, and study exactly how they kill cells at the molecular level. If successful, this work could produce a new class of anticancer drugs that work where existing ones fail. The researchers are already in talks with a commercial partner to move lead compounds toward clinical trials. The project also includes testing in a chick embryo membrane model as a stepping stone to mammalian studies. Because this is preclinical drug development, any impact on patients remains years away, but the multidisciplinary team has a strong track record of publishing in top journals and advancing compounds through the drug-development pipeline.
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The successful student will join a multidisciplinary research team consisting of chemists (Rice and a PDRA funded by the EPSRC award), cell biologists (Allison) and cancer pharmacologists (Phillips) supported by a research technician (Pinder, also part funded via the EPSRC grant). There will therefore be a close collaboration between all elements of the research team, the aim of which is to develop and evaluate the anti-cancer activity of a series of novel cryptands. In addition, we are in discussion with our technology transfer team and a commercial partner to further develop the preclinical program of work required to progress lead compounds into clinical trials. Based on our initial studies, we already have some 'hit' compounds and the student will (i) focus on evaluating the pharmacological properties of our current 'hit' compounds and (ii) determining the activity of novel cryptands synthesised by the chemistry PDRA. Specific studies will focus on establishing structure activity relationships that will help guide further rounds of chemical synthesis and evaluating the mechanism of action of novel cryptands. These studies will use the full range of biological, molecular and pharmacological tools to help unravel the mechanism(s) of action. PhD research will include assessment of whether cryptands can overcome cancer drug resistance to current clinical standard-of-care (SoC) compounds and the evaluation of 'lead' compounds in the in ovo CAM assay as a proof-of-principle in vivo model. In summary, the student will join an established multidisciplinary team of academic and commercial scientists with a track record of publishing work to the highest academic standard including 3* to 4* publications in journals such as Nature Communications and Angewandte Chemie. The student will therefore receive excellent training in all aspects of the preclinical development of novel anticancer drugs leading ultimately to the selection of compounds that will go into clinical trials. From the perspective of generating a PhD thesis, there is considerable scope to explore mechanisms of action of novel compounds thereby creating a specific focus for the student's work leading to a thesis that will make a substantial contribution to knowledge in this field.
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