YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors

Stachelek, Gregory C.; Peterson-Roth, Elizabeth; Liu, Yanfeng; Fernández, Rafael; Pike, Luke; Qian, Jack M.; Abriola, Laura; Hoyer, Daniel; Hungerford, William; Merkel, Janie; Glazer, Peter M.

doi:10.1158/1541-7786.mcr-15-0036

Cited by 19 publications

(14 citation statements)

References 33 publications

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“…Additionally, the synthetic lethality approach to target inhibition of two DNA repair pathways simultaneously is expanding. This is evidenced by the molecule YU238259 that shows synergy to ionizing radiation and potentiates chemotoxicity through inhibition of HDR and shows increased synergy in a BRCA-2 null background (Stachelek et al, 2015). However, in spite of strong pre-clinical data showing highly specific and potent inhibitors, relatively few have been further assessed in clinical trials, many of which have been closed due to toxicities or lack of clinical efficacy.…”

Section: : Dna Damage Response (Ddr) Kinases: Mrn Atm Atr and Chk mentioning

confidence: 99%

DNA repair targeted therapy: The past or future of cancer treatment?

Gavande

VanderVere-Carozza

Hinshaw

et al. 2016

Pharmacology & Therapeutics

332

282

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The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.

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Section: : Dna Damage Response (Ddr) Kinases: Mrn Atm Atr and Chk mentioning

confidence: 99%

DNA repair targeted therapy: The past or future of cancer treatment?

Gavande

VanderVere-Carozza

Hinshaw

et al. 2016

Pharmacology & Therapeutics

332

282

View full text Add to dashboard Cite

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“…Whether PARP inhibitors will be useful in such cancers or if derepression of BRCA-1 expression and induction of resistance will occur remain to be tested. The principle of synthetic lethality is also being explored for other repair defects than BRCA; thus, an HR inhibitor that shows synthetic lethality in BER-defective tumor cells was recently developed [ 244 ].…”

Section: Targets For Radiosensitizationmentioning

confidence: 99%

Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

Maier

Hartmann

Wenz

et al. 2016

IJMS

330

259

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During the last few decades, improvements in the planning and application of radiotherapy in combination with surgery and chemotherapy resulted in increased survival rates of tumor patients. However, the success of radiotherapy is impaired by two reasons: firstly, the radioresistance of tumor cells and, secondly, the radiation-induced damage of normal tissue cells located in the field of ionizing radiation. These limitations demand the development of drugs for either radiosensitization of tumor cells or radioprotection of normal tissue cells. In order to identify potential targets, a detailed understanding of the cellular pathways involved in radiation response is an absolute requirement. This review describes the most important pathways of radioresponse and several key target proteins for radiosensitization.

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“…HU-331 and NU7441 were obtained from SelleckChem (Houston, TX), whereas NK314 was from Adooq Bioscience (Irvine, CA). YU238259 was synthesized according to previous reports [27] by TriMen Chemicals (Lodz, Poland). All of them were made up as stocks and stored at − 20 °C.…”

Section: Viability Assay-cck-8 Kitmentioning

confidence: 99%

Comparison of the effect of three different topoisomerase II inhibitors combined with cisplatin in human glioblastoma cells sensitized with double strand break repair inhibitors

et al. 2019

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Topoisomerase II (Topo2) inhibitors in combination with cisplatin represent a common treatment modality used for glioma patients. The main mechanism of their action involves induction of DNA double-strand breaks (DSBs). DSBs are repaired via the homology-dependent DNA repair (HRR) and non-homologous end-joining (NHEJ). Inhibition of the NHEJ or HRR pathway sensitizes cancer cells to the treatment. In this work, we investigated the effect of three Topo2 inhibitors-etoposide, NK314, or HU-331 in combination with cisplatin in the U-87 human glioblastoma cell line. Etoposide as well as NK314 inhibited Topo2 activity by stabilizing Topo2-DNA cleavable complexes whereas HU-331 inhibited the ATPase activity of Topo2 using a noncompetitive mechanism. To increase the effectiveness of the treatment, we combined cisplatin and Topo2 inhibitor treatment with DSB repair inhibitors (DRIs). The cells were sensitized with NHEJ inhibitor, NU7441, or the novel HRR inhibitor, YU238259, prior to drug treatment. All of the investigated Topo2 inhibitors in combination with cisplatin efficiently killed the U-87 cells. The most cytotoxic effect was observed for the cisplatin + HU331 treatment scheme and this effect was significantly increased when a DRI pretreatment was used; however, we did not observed DSBs. Therefore, the molecular mechanism of cytotoxicity caused by the cisplatin + HU331 treatment scheme is yet to be evaluated. We observed a concentration-dependent change in DSB levels and accumulation at the G2/M checkpoint and S-phase in glioma cells incubated with NK314/cisplatin and etoposide/cisplatin. In conclusion, in combination with cisplatin, HU331 is the most potent Topo2 inhibitor of human glioblastoma cells.

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YU238259 Is a Novel Inhibitor of Homology-Dependent DNA Repair That Exhibits Synthetic Lethality and Radiosensitization in Repair-Deficient Tumors

Cited by 19 publications

References 33 publications

DNA repair targeted therapy: The past or future of cancer treatment?

DNA repair targeted therapy: The past or future of cancer treatment?

Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization

Comparison of the effect of three different topoisomerase II inhibitors combined with cisplatin in human glioblastoma cells sensitized with double strand break repair inhibitors

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