Department of Oncology, Segal Cancer Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University Montreal, QC, Canada.
Front Pharmacol. 2013 Jan 31;4:5. doi: 10.3389/fphar.2013.00005. eCollection 2013.
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.
许多当前的化疗药物通过损伤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。这种治疗方法可以区分地靶向癌症细胞，这些细胞通常与正常组织细胞相比具有快速的细胞分裂。然而，尽管这些治疗方法最初在阻止肿瘤生长和减少肿瘤负担方面非常有效，但最终还是会出现耐药性和疾病进展。这种耐药性的一个主要机制是细胞内 DNA 修复水平的增加。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。这些系统在面对化疗诱导的 DNA 损伤时最初会被淹没，但在持续的选择性压力下会变得更加高效，因此化疗药物的效果会降低。因此，使用靶向特定小分子抑制剂抑制 DNA 修复途径可能会克服细胞对 DNA 损伤化疗药物的耐药性。非同源末端连接是修复 DNA 双链断裂 (DSB) 的主要机制之一，部分受丝氨酸/苏氨酸激酶 DNA 依赖性蛋白激酶 (DNA-PK) 的调节。DNA-PK 全酶作为一种支架蛋白，将断裂的 DNA 末端连接起来，并招募其他修复分子。它还具有可能参与 DNA 损伤信号转导的酶活性。由于其在修复 DSBs 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 抑制剂已被证明在体外协同化疗方面具有疗效。然而，目前已知可特异性抑制 DNA-PK 的化合物受限于较差的药代动力学特性：这些化合物在体内溶解度差，代谢不稳定性高，导致血清半衰期短。未来对 DNA-PK 抑制的改进可能是通过基于最近报道的 DNA-PK 晶体结构设计新分子来实现的。计算机辅助药物设计不仅有助于确定替代代谢不稳定的吗啉代基团的新功能基团，还将有助于设计靶向 DNA-PKcs/Ku80 界面或一个自动磷酸化位点的分子。
