279 Synthesis and Development of Prodrug BCCA621C: a Hypoxia Triggered DNA-PK Inhibitor

Lindquist, Kirstin E.; Cran, Jordan; Kordic, K.; Winters, Geoffrey C.; Chua, Peter; Tan, Jia; Kyle, Alastair H.; Smith, Michael L.; Minchinton, Andrew I.

doi:10.1016/s0959-8049(12)72077-4

Cited by 2 publications

(2 citation statements)

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“…Currently, strategies for overcoming hypoxia-induced radioresistance include hypoxia-activated prodrugs (29), vascular remodeling to increase tumor oxygenation (30), and inhibition of cellular oxygen consumption (31). As hypoxia is a tumor-specific feature, our work here suggests that transient inhibition of DNAPK may be a promising strategy to selectively reverse radioresistance of hypoxic tumor cells and increase therapeutic gain.…”

Section: Discussionmentioning

confidence: 88%

DNAPK Inhibition Preferentially Compromises the Repair of Radiation-induced DNA Double-strand Breaks in Chronically Hypoxic Tumor Cells in Xenograft Models

Jiang

Willmore

Wedge

et al. 2021

Molecular Cancer Therapeutics

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Radiation-induced DNA double strand breaks (DSBs) can be repaired by homologous recombination (HR) and non-homologous end joining (NHEJ). Recently, it has been found that chronic tumor hypoxia compromises HR repair of DNA DSBs, but activates the NHEJ protein DNAPK. We therefore hypothesized that inhibition of DNAPK can preferentially potentiate the sensitivity of chronically hypoxic cancer cells to radiation through contextual synthetic lethality in vivo. In this study, we investigated the impact of DNAPK inhibition by a novel selective DNAPK inhibitor, NU5455, on the repair of radiation-induced DNA DSBs in chronically hypoxic and nonhypoxic cells across a range of xenograft models. We found that NU5455 inhibited DSB repair following radiation in both chronically hypoxic and nonhypoxic tumor cells. Most importantly, the inhibitory effect was more pronounced in chronically hypoxic tumor cells than in nonhypoxic tumor cells. This is the first in vivo study to indicate that DNAPK inhibition may preferentially sensitizes chronically hypoxic tumor cells to radiotherapy, suggesting a broader therapeutic window for transient DNAPK inhibition combined with radiotherapy.

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Section: Discussionmentioning

confidence: 88%

DNAPK Inhibition Preferentially Compromises the Repair of Radiation-induced DNA Double-strand Breaks in Chronically Hypoxic Tumor Cells in Xenograft Models

Jiang

Willmore

Wedge

et al. 2021

Molecular Cancer Therapeutics

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“…in a study assessing the inhibition of DNA double-strand break repair in hypoxic cells by targeting DNA-PK with BCCA621C, a hypoxia-activated inhibitor of DNA-PK. BCCA621C is enzymatically activated, leading in severely hypoxic conditions to radiosensitization of NCI-H460 cells (61). Recent findings indicate that hypoxia induces resistance to alkylating agents via a distinct molecular pathway involving HIF-1α, p53, and the mTOR target gene NDRG1, resulting in stabilization of O6-methylguanine-DNA methyltransferase (AGT), a key enzyme mediating resistance to alkylating agents in glioblastoma and melanoma (62).…”

Section: Clinical–translational Advancesmentioning

confidence: 99%

Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy

Baran

Konopleva

2017

Clinical Cancer Research

110

123

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Hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Hypoxia is associated with insufficient response to standard therapy, resulting in disease progression and curtailed patients’ survival through maintenance of noncycling cancer stem-like cells. A better understanding of the mechanisms and signaling pathways induced by hypoxia is essential to overcoming these effects. Recent findings demonstrate that bone marrow in the setting of hematologic malignancies is highly hypoxic and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor-1alpha (HIF-1α). Solid tumors have also been shown to harbor hypoxic areas, maintaining survival of cancer cells via the HIF-1α pathway. Developing new strategies for targeting hypoxia has become a crucial approach in modern cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments or the hypoxic bone marrow niche via hypoxia-activated prodrugs is increasing. This review discusses the development of the hypoxia-activated prodrugs and their applicability in treating both hematologic malignancies and solid tumors.

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279 Synthesis and Development of Prodrug BCCA621C: a Hypoxia Triggered DNA-PK Inhibitor

Cited by 2 publications

References 0 publications

DNAPK Inhibition Preferentially Compromises the Repair of Radiation-induced DNA Double-strand Breaks in Chronically Hypoxic Tumor Cells in Xenograft Models

DNAPK Inhibition Preferentially Compromises the Repair of Radiation-induced DNA Double-strand Breaks in Chronically Hypoxic Tumor Cells in Xenograft Models

Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy

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