更新于：2024-11-01

APE1 x Top II

更新于：2024-11-01

基本信息

关联

项与 APE1 x Top II 相关的药物

Lucanthone

硫蒽酮

靶点

APE1 x Top II

作用机制

APE1抑制剂 [+1]

在研机构-

原研机构

Arisyn Therapeutics Inc

在研适应症-

非在研适应症

脑癌 [+4]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与 APE1 x Top II 相关的临床试验

NCT02014545 / Withdrawn临床2期IIT

Phase II Trial Evaluating the Addition of Lucanthone to Whole Brain Radiation Therapy in Patients With Brain Metastases From Non-Small Cell Lung Cancer

This is a randomized, double blind placebo controlled study to evaluate safety and efficacy of lucanthone administered as an adjunct to patients receiving whole brain radiation therapy (WBRT) as primary treatment for brain metastases secondary to non-small cell lung cancer.

开始日期2016-01-01

申办/合作机构

Wake Forest School of Medicine

[+1]

NCT01587144 / Terminated临床2期

An International, Multi-Center, Randomized, Double Blind Placebo Controlled Phase II Study to Evaluate the Safety and Efficacy of Lucanthone Administered as an Adjunct to Radiation and Temozolomide for Primary Therapy of Glioblastoma Multiforme

The purpose of the study is to determine the effectiveness of an investigational drug called lucanthone, when combined with temozolomide (TMZ) and radiation in the treatment of Glioblastoma Multiforme (GBM).

开始日期2012-06-19

申办/合作机构

Spectrum Pharmaceuticals, Inc.

100 项与 APE1 x Top II 相关的临床结果

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100 项与 APE1 x Top II 相关的转化医学

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0 项与 APE1 x Top II 相关的专利（医药）

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项与 APE1 x Top II 相关的文献（医药）

2024-01-01·DNA Repair

Interaction of mitoxantrone with abasic sites - DNA strand cleavage and inhibition of apurinic/apyrimidinic endonuclease 1, APE1

Article

作者: Tomar, Rachana ; Stone, Michael P ; Luzadder, Michael M ; McCullough, Amanda K ; Moellmer, Samantha A ; Minko, Irina G ; Lloyd, R Stephen

Mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-anthracene-9,10-dione) is a clinically-relevant synthetic anthracenedione that functions as a topoisomerase II poison by trapping DNA double-strand break intermediates. Mitoxantrone binds to DNA via both stacking interactions with DNA bases and hydrogen bonding with the sugar-phosphate backbone. It has been shown that mitoxantrone inhibits apurinic/apyrimidinic (AP) endonuclease 1 (APE1)-catalyzed incision of DNA containing a tetrahydrofuran (THF) moiety and more recently, that mitoxantrone forms Schiff base conjugates at AP sites in DNA. In this study, mitoxantrone-mediated inhibition of APE1 at THF sites was shown to be consistent with preferential binding to, and thermal stabilization of DNA containing a THF site as compared to non-damaged DNA. Investigations into the properties of mitoxantrone at AP and 3' α,β-unsaturated aldehyde sites demonstrated that in addition to being a potent inhibitor of APE1 at these biologically-relevant substrates (∼ 0.5 μM IC₅₀ on AP site-containing DNA), mitoxantrone also incised AP site-containing DNA by catalyzing β- and β/δ-elimination reactions. The efficiency of these reactions to generate the 3' α,β-unsaturated aldehyde and 3' phosphate products was modulated by DNA structure. Although these cell-free reactions revealed that mitoxantrone can generate 3' phosphates, cells lacking polynucleotide kinase phosphatase did not show increased sensitivity to mitoxantrone treatment. Consistent with its ability to inhibit APE1 activity on DNAs containing either an AP site or a 3' α,β-unsaturated aldehyde, combined exposures to clinically-relevant concentrations of mitoxantrone and a small molecule APE1 inhibitor revealed additive cytotoxicity. These data suggest that in a cellular context, mitoxantrone may interfere with APE1 DNA repair functions.

2021-06-01·SLAS Discovery4区 · 生物学

Unbiased High-Throughput Drug Combination Pilot Screening Identifies Synergistic Drug Combinations Effective against Patient-Derived and Drug-Resistant Melanoma Cell Lines

4区 · 生物学

Article

作者: Johnston, Paul A ; Storkus, Walter J ; Fecek, Ronald J ; Kirkwood, John M ; Close, David A

We describe the development, optimization, and validation of 384-well growth inhibition assays for six patient-derived melanoma cell lines (PDMCLs), three wild type (WT) for BRAF and three with V600E-BRAF mutations. We conducted a pilot drug combination (DC) high-throughput screening (HTS) of 45 pairwise 4×4 DC matrices prepared from 10 drugs in the PDMCL assays: two B-Raf inhibitors (BRAFi), a MEK inhibitor (MEKi), and a methylation agent approved for melanoma; cytotoxic topoisomerase II and DNA methyltransferase chemotherapies; and drugs targeting the base excision DNA repair enzyme APE1 (apurinic/apyrimidinic endonuclease-1/redox effector factor-1), SRC family tyrosine kinases, the heat shock protein 90 (HSP90) molecular chaperone, and histone deacetylases.Pairwise DCs between dasatinib and three drugs approved for melanoma therapy-dabrafenib, vemurafenib, or trametinib-were flagged as synergistic in PDMCLs. Exposure to fixed DC ratios of the SRC inhibitor dasatinib with the BRAFis or MEKis interacted synergistically to increase PDMCL sensitivity to growth inhibition and enhance cytotoxicity independently of PDMCL BRAF status. These DCs synergistically inhibited the growth of mouse melanoma cell lines that either were dabrafenib-sensitive or had acquired resistance to dabrafenib with cross resistance to vemurafenib, trametinib, and dasatinib. Dasatinib DCs with dabrafenib, vemurafenib, or trametinib activated apoptosis and increased cell death in melanoma cells independently of their BRAF status or their drug resistance phenotypes. These preclinical in vitro studies provide a data-driven rationale for the further investigation of DCs between dasatinib and BRAFis or MEKis as candidates for melanoma combination therapies with the potential to improve outcomes and/or prevent or delay the emergence of disease resistance.

2012-12-04·ISRN Molecular Biology

Processing of Damaged DNA Ends for Double-Strand Break Repair in Mammalian Cells

Article

作者: Povirk, Lawrence F.

Most DNA double-strand breaks (DSBs) formed in a natural environment have chemical modifications at or near the ends that preclude direct religation and require removal or other processing so that rejoining can proceed. Free radical-mediated DSBs typically bear unligatable 3′-phosphate or 3′-phosphoglycolate termini and often have oxidized bases and/or abasic sites near the break. Topoisomerase-mediated DSBs are blocked by covalently bound peptide fragments of the topoisomerase. Enzymes capable of resolving damaged ends include polynucleotide kinase/phosphatase, which restores missing 5′-phosphates and removes 3′-phosphates; tyrosyl-DNA phosphodiesterases I and II (TDP1 and TDP2), which remove peptide fragments of topoisomerases I and II, respectively; and the Artemis and Metnase endonucleases, which can trim damaged overhangs of diverse structure. TDP1 as well as APE1 can remove 3′-phosphoglycolates and other 3′ blocks, while CtIP appears to provide an alternative pathway for topoisomerase II fragment removal. Ku, a core DSB joining protein, can cleave abasic sites near DNA ends. The downstream processes of patching and ligation are tolerant of residual damage and can sometimes proceed without complete damage removal. Despite these redundant pathways for resolution, damaged ends appear to be a significant barrier to rejoining, and their resolution may be a rate-limiting step in repair of some DSBs.