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A medicinal chemist at the ¹û¶³Ó°Ôº School of Pharmacy, Dr Wells has developed a range of small-molecule compounds for cancer targets. Notably, he has explored the potential of cancer chemoprevention - the idea that boosting a cell's anti-oxidant defences could protect cells from DNA damage and hence cut the risk of cancer-causing mutations.

One particular focus has been a protein known as Nrf2, a transcription factor activated by cellular stress that drives the expression of a multitude of cytoprotective genes. In the absence of cellular stress, Nrf2 activity is repressed by the binding of an inhibitor protein, Keap1. Over a decade or so, Dr Wells and colleagues developed a range of peptides and small-molecule compounds that block the interaction between Nrf2 and Keap1, freeing up Nrf2 to drive its transcriptional stress response programme [1-3].

However, the prospects of Nrf2 activation for chemoprevention have been tempered by the suggestion that it may have unwanted effects on established tumours, rendering them less sensitive to other cytotoxic agents. Dr Wells and other are now exploring the potential use of Nrf2 activators in protection against neurodegenerative disease, based on their ability to promote the disposal of abnormal cellular proteins and organelles.

A second target of interest has been thioredoxin reductase, an enzyme with a key role in anti-oxidant defence. Cellular metabolism is frequently abnormal in cancer cells, leading to the generation of increased levels of reactive oxygen species. In response, established tumours typically have elevated levels of anti-oxidant defences, and disabling these defences could compromise cancer cell survival. With colleagues in Singapore, Dr Wells has developed and evaluated small-molecule compounds targeting thioredoxin reductase that show encouraging levels of cytotoxicity on a range of cultured cancer cells [4].

More recently, Dr Wells has developed a promising strand of work on kinesins, motor proteins with a variety of roles including separation of chromosomes in cell division. Kinesin over-expression is seen in a range of cancers, notably bladder cancer. In collaboration with Professor Frank Kozielski at the ¹û¶³Ó°Ôº School of Pharmacy, Dr Wells is using an understanding of the X-ray crystallographic structure of kinesins to refine the design of small-molecule inhibitory compounds as potential anti-cancer agents.

1. Hancock R, Schaap M, Pfister H, Wells G. Org Biomol Chem. 2013;11(21):3553-7.
2. Nagle AA et al. ChemMedChem. 2014;9(8):1763-74.
3. Bertrand HC et al. J Med Chem. 2015;58(18):7186-94.
4. Kaminska KK et al. Oncotarget. 2016;7(26):40233-40251.