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• W2917680132 abstract "406 An important determinant of the susceptibility of cancer cells to DNA damaging anti-cancer therapeutics is the ability of the cells to repair the DNA damage inflicted upon them. It has therefore been proposed that inhibition of DNA repair processes could lead to the potential therapeutic endpoints of radio- and chemosensitisation. A key kinase involved in the detection, signaling and repair of DNA double strand breaks (DSBs) is the DNA-dependent protein kinase (DNA-PK). DNA-PK is intimately involved in the repair of DNA DSBs by the process of non-homologous end joining (NHEJ). Inhibition of DNA-PK activity through the probe compounds LY294002 (non-selective, IC50 1.5uM) and NU7441 (selective; IC50=13nM) has previously been shown to lead to cellular radio- and chemo-sensitisation. Through the generation of a focused compound library based around NU7441 to improve this compound’s overall biopharmaceutical properties, we have identified the compound KU-0060648. This agent exhibits 20-1000 fold selectivity for DNA-PK over related PIKK enzymes and PI3K family members. KU-0060648 was found not to radio-potentiate DNA-PKcs deficient cells, further highlighting its selective nature in vitro. KU-0060648 was able to inhibit the serine-2056 auto-phosphorylation site of DNA-PKcs with an IC50 of 60nM in FaDu cells and abrogated the phosphorylation of H2AX in response to ionizing radiation (IR). Doses of as little as 100nM were found to radiosensitise FaDu cells (Enhancement Ratio at 10% survival of 2.3), using clonogenic assays as an endpoint. KU-0060648 was able to radiopotentiate 2Gy of IR after only 2 hours of exposure, highlighting its role in disrupting the NHEJ dependent fast component of DNA DSB repair. KU-0060648 was also found to preferentially kill BRCA2-defective and ATM-defective cells in combination with IR or etoposide, suggesting that DNA repair defective tumour cells may provide a therapeutic advantage for this class of agent. Pharmacokinetic profiling of KU-0060648 in mice revealed that the compound showed 100% bioavailability, with a t1/2 of 142 minutes after p.o. dosing. In a fractionated IR (5x2Gy) FaDu xenograft model, KU-0060648, dosed at either 10 or 25mg/kg qd 30 minutes before IR caused significant growth delay compared to the control 5x2Gy group. PK/PD relationships were established to define the exposures and level of DNAPK inhibition required for effective radiosensitisation. Our results to date support the further in vivo evaluation of this novel class of agent as a radiosensitiser prior to clinical evaluation." @default.
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• W2917680132 date "2008-05-01" @default.
• W2917680132 modified "2023-09-23" @default.
• W2917680132 title "Potent in vitro and in vivo radiosensitisation by the selective DNA-dependent protein kinase inhibitor KU-0060648" @default.
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