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BPR1K653 是一种新型的 Aurora 激酶抑制剂，对 MDR1（P-糖蛋白 170）介导的多药耐药癌细胞具有很强的抗增殖活性。

BPR1K653, a novel Aurora kinase inhibitor, exhibits potent anti-proliferative activity in MDR1 (P-gp170)-mediated multidrug-resistant cancer cells.

机构信息

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan ROC.

出版信息

PLoS One. 2011;6(8):e23485. doi: 10.1371/journal.pone.0023485. Epub 2011 Aug 24.

DOI:10.1371/journal.pone.0023485
PMID:21887256
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3160846/
Abstract

BACKGROUND

Over-expression of Aurora kinases promotes the tumorigenesis of cells. The aim of this study was to determine the preclinical profile of a novel pan-Aurora kinase inhibitor, BPR1K653, as a candidate for anti-cancer therapy. Since expression of the drug efflux pump, MDR1, reduces the effectiveness of various chemotherapeutic compounds in human cancers, this study also aimed to determine whether the potency of BPR1K653 could be affected by the expression of MDR1 in cancer cells.

PRINCIPAL FINDINGS

BPR1K653 specifically inhibited the activity of Aurora-A and Aurora-B kinase at low nano-molar concentrations in vitro. Anti-proliferative activity of BPR1K653 was evaluated in various human cancer cell lines. Results of the clonogenic assay showed that BPR1K653 was potent in targeting a variety of cancer cell lines regardless of the tissue origin, p53 status, or expression of MDR1. At the cellular level, BPR1K653 induced endo-replication and subsequent apoptosis in both MDR1-negative and MDR1-positive cancer cells. Importantly, it showed potent activity against the growth of xenograft tumors of the human cervical carcinoma KB and KB-derived MDR1-positive KB-VIN10 cells in nude mice. Finally, BPR1K653 also exhibited favorable pharmacokinetic properties in rats.

CONCLUSIONS AND SIGNIFICANCE

BPR1K653 is a novel potent anti-cancer compound, and its potency is not affected by the expression of the multiple drug resistant protein, MDR1, in cancer cells. Therefore, BPR1K653 is a promising anti-cancer compound that has potential for the management of various malignancies, particularly for patients with MDR1-related drug resistance after prolonged chemotherapeutic treatments.

摘要

背景

Aurora 激酶的过度表达促进了细胞的肿瘤发生。本研究旨在确定新型泛 Aurora 激酶抑制剂 BPR1K653 的临床前特征，作为抗癌治疗的候选药物。由于药物外排泵 MDR1 的表达降低了各种化疗化合物在人类癌症中的有效性，因此本研究还旨在确定 BPR1K653 的效力是否会受到癌细胞中 MDR1 表达的影响。

主要发现

BPR1K653 在体外以低纳摩尔浓度特异性抑制 Aurora-A 和 Aurora-B 激酶的活性。在各种人类癌细胞系中评估了 BPR1K653 的抗增殖活性。集落形成试验的结果表明，BPR1K653 针对多种癌细胞系具有强大的靶向作用，无论组织来源、p53 状态或 MDR1 的表达如何。在细胞水平上，BPR1K653 在 MDR1 阴性和 MDR1 阳性癌细胞中均诱导内复制和随后的细胞凋亡。重要的是，它对裸鼠中人类宫颈癌 KB 及其衍生的 MDR1 阳性 KB-VIN10 细胞的异种移植肿瘤的生长表现出强大的活性。最后，BPR1K653 在大鼠中也表现出良好的药代动力学特性。

结论和意义

BPR1K653 是一种新型有效的抗癌化合物，其效力不受癌细胞中多药耐药蛋白 MDR1 的表达影响。因此，BPR1K653 是一种有前途的抗癌化合物，具有治疗各种恶性肿瘤的潜力，特别是对于经过长期化疗治疗后出现 MDR1 相关耐药的患者。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/76610eff3ce1/pone.0023485.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/b300ec7d5d8d/pone.0023485.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/ade6a345cd21/pone.0023485.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/74f81bd80638/pone.0023485.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/04d6c8c0bef2/pone.0023485.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/ac963f105afa/pone.0023485.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/76610eff3ce1/pone.0023485.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/b300ec7d5d8d/pone.0023485.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/ade6a345cd21/pone.0023485.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/74f81bd80638/pone.0023485.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/04d6c8c0bef2/pone.0023485.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/ac963f105afa/pone.0023485.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/270d/3160846/76610eff3ce1/pone.0023485.g006.jpg

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1
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2
Aurora kinase inhibitor patents and agents in clinical testing: an update (2009-10).极光激酶抑制剂专利和临床试验中的药物：最新进展（2009-10）。
Expert Opin Ther Pat. 2011 Jun;21(6):857-84. doi: 10.1517/13543776.2011.574614.
3
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开发一种用于癌症治疗的癌细胞自激活和 miR-125a-5p 表达的多药理纳米药物。
Int J Mol Med. 2022 Aug;50(2). doi: 10.3892/ijmm.2022.5158. Epub 2022 Jun 15.
4
FTY720 in resistant human epidermal growth factor receptor 2-positive breast cancer.依维莫司联合曲妥珠单抗治疗人表皮生长因子受体 2 阳性转移性乳腺癌的临床观察
Sci Rep. 2022 Jan 7;12(1):241. doi: 10.1038/s41598-021-04328-y.
5
Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy.靶向 AURKA 在癌症中的作用：癌症治疗的分子机制和机会。
Mol Cancer. 2021 Jan 15;20(1):15. doi: 10.1186/s12943-020-01305-3.
6
Discovery of BPR1K871, a quinazoline based, multi-kinase inhibitor for the treatment of AML and solid tumors: Rational design, synthesis, in vitro and in vivo evaluation.BPR1K871的发现，一种用于治疗急性髓系白血病和实体瘤的喹唑啉类多激酶抑制剂：合理设计、合成、体外和体内评价
Oncotarget. 2016 Dec 27;7(52):86239-86256. doi: 10.18632/oncotarget.13369.
7
Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma.骨肉瘤分子靶向治疗的当前进展与未来展望
Int J Mol Sci. 2016 Apr 6;17(4):506. doi: 10.3390/ijms17040506.
8
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9
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8
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9
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10
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