PARP is a family of enzymes that help repair DNA when it is damaged; they also aid the repair of cancer cells, so the development of targeted PARP inhibitors provides a means for effective cancer treatments.
Existing PARP inhibitors have shown to be ineffective and lack selectivity and some compounds can contribute to toxicity, most of which are hematological in nature. The catalytic properties of some PARP inhibitors can cause them to remain bound to the DNA, causing damage in the shape of lesions and double-strand breaks, which eventually leads to cell death. When combined with mutated BRCA, which are tumour suppressor genes, PARP inhibitors can trap PARP 1 & 2 to DNA.
A team of scientists from AstraZeneca used macromolecular crystallography (MX) at Diamond to study the structure and properties of a potent and selective PARP1 inhibitor and PARP 1-DNA trapper. The aim is to develop improved therapies with less hematological toxicity, and which would have the potential to be more effective in against BRCA mutants.
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