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Pairing up against cancer
01 April 2010
Researchers from the University of Bath, UK and their collaborators have demonstrated a novel approach to anticancer drug design that combines the active fragments of two known anticancer agents that work in different ways to kill cancer cells. In doing so, Barry Potter and his team have discovered a new family of compounds that could be more effective than either of the parent molecules while also overcoming many of their drawbacks.
The new 'chimeric' drugs combine parts of the anticancer agents 2-methoxyestradiol and colchicine. 2-Methoxyestradiol is an effective antitumor agent but is rapidly metabolised in the body, while colchicine is a powerful molecule that can stop cancerous cells dividing, but its use is limited as its potency is low compared with its toxicity.
Chimeras are animals that have two or more different populations of genetically distinct cells, similar to the design of the chimeric drugs
Once the key features from both drug molecules were combined the researchers added a sulfamoyl group to improve the drug's bioavailability. In doing so, Potter has generated new 'chimeric drug structures that show improved in vitro activities against prostate and breast cancer cell lines - in one case, creating a drug that was around 30 times more active against prostate cancer cells than 2-methoxyestradiol.
Nick Lawrence, an expert in the development of new anticancer drugs at the University of South Florida in Tampa, US, comments 'this is a very nice approach to the development of new microtubule disruptors. The combination of structural features taken from a new steroidal agent and those of the archetypal tubulin-binding agent colchicine is intriguing. That this has lead to a compound that has significant antitumor effects is extremely promising.'
Looking to the future Potter's team plans to investigate the efficacy and potential in vivo of these chimeric compounds. When asked if he plans to employ this chimeric drug design strategy to other drug targets, Potter responds 'it is an interesting strategy with significant broader potential, but as always in drug discovery there is a degree of good fortune'
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Link to journal article
Chimeric microtubule disruptors
Mathew P. Leese, Fabrice Jourdan, Meriel R. Kimberley, Gyles E. Cozier, Nethaji Thiyagarajan, Chloe Stengel, Sandra Regis-Lydi, Paul A. Foster, Simon P. Newman, K. Ravi Acharya, Eric Ferrandis, Atul Purohit, Michael J. Reed and Barry V. L. Potter, Chem. Commun., 2010, 46, 2907
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