Abstract A116: Radio- and chemosensitization through inhibition of DNA-PK by KU-0060648
| Autor: | Nahida Parveen, Aaron Cranston, Niall M. B. Martin, William Deacon, Kerry Shea, Graeme C. M. Smith, Mark Albertella, Marcus Peacock, Julia Bardos, Keith Allan Menear |
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| Rok vydání: | 2009 |
| Předmět: | |
| Zdroj: | Molecular Cancer Therapeutics. 8:A116-A116 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | DNA double strand breaks (DSBs) are profoundly cytotoxic unless rapidly repaired. Non-homologous end joining (NHEJ) is the predominant pathway of DSB repair in mammalian cells. DNA-dependent protein kinase (DNA-PK), a member of the PI3-kinase like kinase (PIKK) family, is an essential component of NHEJ, and DNA-PK inhibition in combination with radio- or chemotherapy therefore represents an attractive therapeutic approach in cancer therapy. Through medicinal chemistry, a series of DNA-PK inhibitors of increasing potency was identified, resulting in KU-0060648, a potent DNA-PK inhibitor with an IC50 value of 10nM against the enzyme and high selectivity for DNA-PK over other PIKKs and a panel of 60 kinases. In cellular assays, KU-0060648 significantly increases cell death induced by ionising radiation (IR) or chemotherapeutic treatments, such as doxorubicin or etoposide. KU-0060648 does not sensitise DNA-PK-deficient cells to IR or chemotherapeutic treatments, further highlighting its selective nature. The compound was also found to preferentially kill DNA repair-defective cells in combination with IR or chemotherapy, indicating a therapeutic advantage for this class of agent in DNA repair-compromised tumor cells. Auto-phosphorylation of DNA-PK at serine 2056 is inhibited by KU-0060648, and significant changes in IR- or chemotherapy-induced H2AX- and KAP-1 phosphorylation in the presence KU-0060648 over time clearly indicates inhibition of DNA damage repair by this compound. Pharmacokinetic and pharmacodynamic profiling of KU-0060648 revealed that the compound has very good oral bioavailability and a favourable half life. In a fractionated IR xenograft model, dosing with KU-0060648 caused significant tumor growth delay compared to the control group. PK/PD relationships were established to define the exposures and level of DNA-PK inhibition required for effective radiosensitisation. Our results to date support further in vitro and in vivo evaluation of this novel class of therapeutic agents as a potential clinical radio- and chemosensitiser. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A116. |
| Databáze: | OpenAIRE |
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