Researchers at Dublin City University (DCU) have discovered a new method to prepare DNA damaging drug molecules. The long-term goal of the work is to provide effective, new personalised cancer treatments with lower side effects.
The discovery was made thanks to the efforts of DCU’s Dr Andrew Kellett and his team of researchers who collaborated with researchers from Sweden’s Chalmers University of Technology.
The research teams invented the ‘click and cut’ method to address the challenge presented by increasing patient resistance to metal-based drugs, which are often used to treat cancers.
The method involves the attachment of metal ion binding groups to a central scaffold using click chemistry. With this approach, the team prepared a library of drug candidates and identified a lead agent with high potential for treating cancer.
From the entire screen, one compound was identified to bind strongly with copper ions and produce a unique type of DNA damage that is not possible to achieve 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 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.
Speaking about the discovery, Kellett said: “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.”
New therapies for difficult-to-treat cancers such as triple-negative breast cancer or glioblastoma multiforme are highly sought after due to the lack of treatments currently available.
The research team now aims to expand the new method and develop more therapies targeted at specific cancer-causing genes. Plans are also underway to develop second generation chemotherapeutics with improved properties.
The research teams’ efforts have produced a paper titled ‘Click and Cut: A Click Chemistry Approach to Developing Oxidative DNA Damaging Agents,’ which has been published in the Nucleic Acids Research journal. It is an open access publication.
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