Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.
Small Molecules, Inhibitors of DNA-PK, Targeting DNA Repair, and Beyond.
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DOI：
10.3389/fphar.2013.00005
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发表时间：
2013
影响因子：
5.6
通讯作者：
Aloyz R
中科院分区：
文献类型：
--
作者：
Davidson D;Amrein L;Panasci L;Aloyz R
目前许多化疗药物通过破坏快速分裂细胞中的基因组 DNA 来发挥作用，最终导致细胞死亡。这种治疗方法针对癌细胞，与正常组织细胞相比，癌细胞通常表现出快速细胞分裂。然而，尽管这些治疗最初可有效阻止肿瘤生长并减轻肿瘤负荷，但最终会出现耐药性和疾病进展。这种抵抗的一个主要机制是细胞 DNA 修复水平的提高。大多数细胞都有复杂的机制来修复由于环境暴露或正常代谢过程而发生的 DNA 损伤。这些系统最初在面临化疗引起的 DNA 损伤时不堪重负，但在持续的选择压力下变得更加有效，结果化疗变得不那么有效。因此，使用靶标特异性小分子抑制剂抑制 DNA 修复途径可能会克服细胞对 DNA 损伤化疗的耐药性。非同源末端连接是修复 DNA 双链断裂 (DSB) 的主要机制，部分由丝氨酸/苏氨酸激酶、DNA 依赖性蛋白激酶 (DNA-PK) 调节。 DNA-PK 全酶充当支架蛋白，束缚断裂的 DNA 末端并招募其他修复分子。它还具有可能参与 DNA 损伤信号传导的酶活性。由于其在 DSB 修复中的核心作用，DNA-PK 一直是许多小分子研究的焦点。在这些研究中，特定的 DNA-PK 抑制剂已显示出在体外协同化疗的功效。然而，目前已知的特异性抑制DNA-PK的化合物受到药代动力学较差的限制：这些化合物溶解度差，体内代谢不稳定性高，导致血清半衰期短。未来 DNA-PK 抑制的改进可能会通过根据最近报道的 DNA-PK 晶体结构设计新分子来实现。基于计算机的药物设计不仅有助于识别新的功能部分来取代代谢不稳定的吗啉代基团，而且还将有助于设计靶向 DNA-PKcs/Ku80 界面或自磷酸化位点之一的分子。
Many current chemotherapies function by damaging genomic DNA in rapidly dividing cells ultimately leading to cell death. This therapeutic approach differentially targets cancer cells that generally display rapid cell division compared to normal tissue cells. However, although these treatments are initially effective in arresting tumor growth and reducing tumor burden, resistance and disease progression eventually occur. A major mechanism underlying this resistance is increased levels of cellular DNA repair. Most cells have complex mechanisms in place to repair DNA damage that occurs due to environmental exposures or normal metabolic processes. These systems, initially overwhelmed when faced with chemotherapy induced DNA damage, become more efficient under constant selective pressure and as a result chemotherapies become less effective. Thus, inhibiting DNA repair pathways using target specific small molecule inhibitors may overcome cellular resistance to DNA damaging chemotherapies. Non-homologous end joining a major mechanism for the repair of double-strand breaks (DSB) in DNA is regulated in part by the serine/threonine kinase, DNA dependent protein kinase (DNA-PK). The DNA-PK holoenzyme acts as a scaffold protein tethering broken DNA ends and recruiting other repair molecules. It also has enzymatic activity that may be involved in DNA damage signaling. Because of its’ central role in repair of DSBs, DNA-PK has been the focus of a number of small molecule studies. In these studies specific DNA-PK inhibitors have shown efficacy in synergizing chemotherapies in vitro. However, compounds currently known to specifically inhibit DNA-PK are limited by poor pharmacokinetics: these compounds have poor solubility and have high metabolic lability in vivo leading to short serum half-lives. Future improvement in DNA-PK inhibition will likely be achieved by designing new molecules based on the recently reported crystallographic structure of DNA-PK. Computer based drug design will not only assist in identifying novel functional moieties to replace the metabolically labile morpholino group but will also facilitate the design of molecules to target the DNA-PKcs/Ku80 interface or one of the autophosphorylation sites.
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DOI：
10.1093/jnci/djp235
发表时间：
2009-09-02
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Cardoso F;Bedard PL;Winer EP;Pagani O;Senkus-Konefka E;Fallowfield LJ;Kyriakides S;Costa A;Cufer T;Albain KS;ESO-MBC Task Force
通讯作者：
ESO-MBC Task Force
影响因子：
16
作者：
Callen, Elsa;Jankovic, Mila;Wong, Nancy;Zha, Shan;Chen, Hua-Tang;Difilippantonio, Simone;Di Virgilio, Michela;Heidkamp, Gordon;Alt, Frederick W.;Nussenzweig, Andre;Nussenzweig, Michel
通讯作者：
Nussenzweig, Michel
DNA-PKcs 在响应 DNA 损伤和细胞周期进展的 H2AX 磷酸化调节中起主导作用。
影响因子：
--
作者：
An J;Huang YC;Xu QZ;Zhou LJ;Shang ZF;Huang B;Wang Y;Liu XD;Wu DC;Zhou PK
通讯作者：
Zhou PK
影响因子：
2.7
作者：
Amrein, Lilian;Davidson, David;Panasci, Lawrence
通讯作者：
Panasci, Lawrence
影响因子：
5.2
作者：
Azad, Arun;Jackson, Susan;Solomon, Benjamin
通讯作者：
Solomon, Benjamin