Researchers at Dublin City University (DCU) have discovered a new method to prepare DNA damaging drug molecules. It is hoped that this work will lead to new personalised cancer treatments that produce lower side-effects.
Metal-based drugs deliver first-line treatment against many forms of cancer, but resistance often builds up leading to their inactivation. In order to widen treatment possibilities, particularly against difficult-to-treat cancers such as triple-negative breast cancer, new therapies with improved or evasive modes of action are required.
Working with a team from Chalmers University of Technology (CUT) in Sweden, the DCU researchers set out to address this challenge by developing the ‘Click and Cut’ method. It involves the attachment of metal ion binding groups to a central scaffold using click chemistry.
Using this approach, they prepared a number of drug candidates, screening them together with different types of metal ions. From this screen, one compound was identified that had a high potential for treating human cancer. It was found to bind strongly with copper ions and produce a unique type of DNA damage that is not possible with existing metal-based drugs.
The compound was then identified to produce DNA damage within primary human cells. By isolating the DNA from these cells, single molecule imaging was performed to visualise the amount of damage and the type of DNA repair (base excision repair - BER) enzymes activated in response.
The results were encouraging and showed the compound could produce a high amount of specific damage, which placed it in a unique chemotherapeutic class.
“These results are promising and indicate a new avenue for preparing unique types of drug molecules. Although click chemistry has an extensive range of applications, particularly in the field of nucleic acid chemistry, it has not yet been widely considered as a way to construct DNA-damaging metallodrugs,” explained lead DCU researcher, Dr Andrew Kellett.
The researchers now aim to expand this method and develop new therapies directed towards specific cancer-causing genes. Plans are also underway to develop second generation chemotherapeutics with improved properties.
Details of the Click and Cut research are published in the journal, Nucleic Acids Research, and can be viewed here.