A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency.
A DNA/HDAC dual-targeting drug CY190602 with significantly enhanced anticancer potency.
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DNA/HDAC双靶向药物CY190602显着增强抗癌效力
DOI：
10.15252/emmm.201404580
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发表时间：
2015-04
影响因子：
11.1
通讯作者：
Jiang H
中科院分区：
文献类型：
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作者：
Liu C;Ding H;Li X;Pallasch CP;Hong L;Guo D;Chen Y;Wang D;Wang W;Wang Y;Hemann MT;Jiang H
基因毒性药物是人类癌症的主要治疗方式；然而，癌细胞固有的DNA修复能力往往增加了致命的门槛，使这些药物无效。hdac在DNA修复中的新作用为改进传统的基因毒性药物提供了新的机会。在这里，我们报道了CY190602的开发和特性，CY190602是一种新型苯达莫司汀衍生药物，具有显著增强的抗癌能力。我们发现CY190602的效力增强可归因于其新获得的抑制hdac的能力。利用这种新的DNA/HDAC双靶向药物作为工具，我们进一步探索了HDAC在DNA修复中的作用。我们发现，HDAC活性对于参与DNA合成和修复的几个基因的表达至关重要，包括TYMS、Tip60、CBP、EP300和MSL1。重要的是，CY190602是此类DNA/HDAC双靶向药物的首个同类例子，在体外和体内均表现出显著增强的抗癌活性。这些发现为将HDAC抑制片段加入到基因毒性药物中，从而克服癌细胞的修复能力提供了依据。系统地开发类似的DNA/HDAC双靶向药物可能为改善癌症治疗提供了新的机会。
Genotoxic drugs constitute a major treatment modality for human cancers; however, cancer cells' intrinsic DNA repair capability often increases the threshold of lethality and renders these drugs ineffective. The emerging roles of HDACs in DNA repair provide new opportunities for improving traditional genotoxic drugs. Here, we report the development and characterization of CY190602, a novel bendamustine‐derived drug with significantly enhanced anticancer potency. We show that CY190602's enhanced potency can be attributed to its newly gained ability to inhibit HDACs. Using this novel DNA/HDAC dual‐targeting drug as a tool, we further explored HDAC's role in DNA repair. We found that HDAC activities are essential for the expression of several genes involved in DNA synthesis and repair, including TYMS, Tip60, CBP, EP300, and MSL1. Importantly, CY190602, the first‐in‐class example of such DNA/HDAC dual‐targeting drugs, exhibited significantly enhanced anticancer activity in vitro and in vivo. These findings provide rationales for incorporating HDAC inhibitory moieties into genotoxic drugs, so as to overcome the repair capacity of cancer cells. Systematic development of similar DNA/HDAC dual‐targeting drugs may represent a novel opportunity for improving cancer therapy.
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影响因子：
82.9
作者：
Janes, Matthew R.;Limon, Jose J.;So, Lomon;Chen, Jing;Lim, Raymond J.;Chavez, Melissa A.;Vu, Collin;Lilly, Michael B.;Mallya, Sharmila;Ong, S. Tiong;Konopleva, Marina;Martin, Michael B.;Ren, Pingda;Liu, Yi;Rommel, Christian;Fruman, David A.
通讯作者：
Fruman, David A.
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
20.3
作者：
Boulos, Nidal;Mulder, Heather L.;Williams, Richard T.
通讯作者：
Williams, Richard T.
影响因子：
20.3
作者：
Flinn, Ian W.;van der Jagt, Richard;Burke, John M.
通讯作者：
Burke, John M.
影响因子：
64.8
作者：
通讯作者：
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