Download PARP inhibitors for cancer therapy Nicola Curtin Newcastle

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PARP inhibitors for cancer therapy
Nicola Curtin
Newcastle University, Newcastle upon Tyne, UK
Poly(ADP-ribose) polymerase (PARP)is a DNA damage-activated
enzyme that catalyses the formation of ADP ribose polymers
from NAD+. It plays a key role in the repair of DNA breaks and
PARP inhibitors (PARPi) were first developed with the purpose of
increasing the persistence of DNA damage in order to increase
the antitumour activity of DNA damaging anticancer agents.
Over the last 3 decades PARPi of increasing potency have been
developed, virtually all contain the nicotinamide pharmacophore.
PARPi increase the persistence of DNA single and double strand
breaks and enhance the cytotoxicity and antitumour activity of
DNA methylating agents, topoisomerase I poisons and ionising
radiation. However, it was the discovery that PARPi selectively
killed cells and tumour xenografts defective in homologous
recombination repair (HRR) that led to a heightened interest in
PARPi. This phenomenon of “synthetic lethality”, where inactivation of one of 2 complementary pathways alone does not
affect viability but inactivation of both together is lethal, is a new
paradigm in cancer therapy. HRR defects are relatively common
in tumours, the classic example being mutations in the breast and
ovarian cancer susceptibility genes, BRCA1 and BRCA2. The first
cancer patient was treated with a PARPi in 2003 and there are
now 9 PARPi undergoing clinical evaluation as single agent or in
combination studies.