Cancer drug precursor designed to reduce toxic side effects
Edinburgh researchers developed an orally bioavailable palladium activated 5-Fluorouracil precursor designed to evade anabolic and catabolic drug pathways: March 2022
Toxic side effects often limit utility of cancer therapeutics. In some cases, they may even be life threatening preventing many patients from receiving most effective treatment. Consequently, administration of cancer chemotherapy in a least harmful way without causing any side effects represents the ultimate goal for many cancer clinicians and medicinal chemists. Researchers in our Centre are at the forefront of developing bioorthogonal chemistry approaches that, one day, could bring us closer towards achieving this goal.
The term bioorthogonal chemistry refers to chemical reactions that can occur inside living systems without interfering with native biochemical processes. The Centre’s Innovative Therapeutics group and their collaborators pioneered the use of catalytic reactions mediated by transition metals such as palladium (Pd) and gold to enable transformation of specially designed harmless chemical compounds (prodrugs) into biologically active drugs in direct proximity of the tumour site, thus reducing harmful effects on other parts of the body. Importantly, they have already proven utility of these approaches in different preclinical model systems. The group, led by Professor Asier Unciti-Broceta, continues cutting-edge research in this field and provides steady progress, possibly paving the way for this new technology to enter clinical trials in the future. In a recent study, titled “A 5-FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo”, the team described development of a palladium activated prodrug of 5-Fluorouracil (5-FU) with very unique properties.
5-FU, and the 5-FU precursors tegafur and capecitabine, belong to the most prescribed cancer chemotherapies. They are used to treat multiple cancer types including breast, colon and skin cancers (as a single agent or in combination with other therapeutics). 5-FU exerts its anticancer effects through inhibition of the enzyme thymidylate synthase and incorporation of its metabolites into RNA and DNA molecules. Unfortunately, it is normally administered as intravenous injection or infusion, causing multiple undesired side effects. 5-FU toxicity is responsible for numerous deaths each year.
Aiming to improve chemotherapy regimens by controlling where and when anticancer drugs are released, our researchers and their collaborators developed an orally bioavailable precursor of 5-FU that is selectively activated by Pd catalysis. Importantly, the prodrug was designed in such a way that it displayed increased stability to degradation and hepatic clearance, thereby showing improved in vivo drug metabolism and pharmacokinetics (DMPK) properties relative to 5-FU. The study demonstrated (for the ﬁrst time), that an inactive drug precursor can be administered orally and activated inside a tumour (in an animal xenograft model) by intratumourally implanted Pd catalysts.
The work, published in the Journal of Medicinal Chemistry, was driven by postdoctoral researchers Catherine Adam and Thomas Bray. It was supported by funding from Engineering and Physical Sciences Research Council, European Commission, Medical Research Scotland and Medical Research Council.
This is a very exciting study because it demonstrates that bioorthogonal strategies can be used not only to improve the tolerability of approved therapeutics, but also to solve inherent pharmacokinetics issues of those drugs, potentially leading to more favourable ways of drug administration.
Article in the Journal of Medicinal Chemistry: https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01733
Innovative Therapeutics Group web page: https://www.ed.ac.uk/cancer-centre/research/unciti-broceta-group
Information about 5-Fluorouracil: https://www.cancerresearchuk.org/about-cancer/cancer-in-general/treatment/cancer-drugs/drugs/fluorouracil
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