Poly(ADP-ribose)polymerase-1 (PARP1) is a DNA repair enzyme highly expressed in the nuclei of mammalian cells. PARP inhibitors, moreover, can be used to induce synthetic lethality in cells where the homologous recombination (HR) pathway is deficient[2]. PARP enzymes are broadly involved in the cellular response to DNA damage. PARP-1 is the chief human PARP enzyme involved in the DNA damage response, acting as a first responder that detects DNA strand breaks, and contributes to repair pathway choice and the efficiency of repair through modulation of chromatin structure and through interaction with and modification of a multitude of DNA repair factors[3]. PARP inhibitors can trap the PARP-1 protein at a single-stranded break/DNA lesion and disrupt its catalytic cycle, ultimately leading to replication fork progression and consequent double-strand breaks. [4].BRCA1 and BRCA2 proteins are essential for high-fidelity repair of double-strand breaks of DNA through the homologous recombination repair (HRR) pathway. Deficiency in HRR (HRD) is a target for PARP inhibitors[5]. Inhibition of PARP function results in cell death in HR-deficient tumors, and sensitizes tumor cells to cytotoxic agents that induce DNA damage[6]. AZ9482 is a selective and potent inhibitor of PARP featuring an amide linkage to a 2-piperazinyl-3-cyano-pyridine. AZ9482 exhibits very potent activity of centrosome declustering with EC50 of < 18 nM in HeLa cells[7].
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