Mechanism of Glutathione Transferase P1-1-Catalyzed Activation of the Prodrug Canfosfamide (TLK286, TELCYTA)
Mechanism of Glutathione Transferase P1-1-Catalyzed Activation of the Prodrug Canfosfamide (TLK286, TELCYTA)
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DOI：
10.1021/bi4005705
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发表时间：
2013-11-12
期刊：
影响因子：
2.9
通讯作者：
Mannervik, Bengt
中科院分区：
文献类型：
--
作者：
Dourado, Daniel F. A. R.;Fernandes, Pedro Alexandrino;Mannervik, Bengt
坎磷酰胺（TLK 286，TELCYTA）是一种前药，经谷胱甘肽转移酶P1-1（GST P1-1）活化后可产生抗癌烷化剂和谷胱甘肽衍生物。在化疗中使用TLK 286的基本原理是过表达GST P1-1的肿瘤细胞将局部暴露于释放的烷化剂，对周围正常组织的附带毒性有限。TLK 286已在II期和III期临床试验中证明了作为单药和与其他化疗药物联合治疗恶性肿瘤（如卵巢癌、非小细胞肺癌和乳腺癌）的临床效果。尽管取得了这些有希望的结果，但该前药GST P1-1激活的详细机制尚未阐明。在这里，我们提出了一个机制的TLK 286激活GST P1-1的基础上的密度泛函理论（DFT）和平均力（PMF）计算的潜力。催化水分子通过在活性位点Tyr 7羟基与TLK 286的砜和COO-基团之间形成分子间相互作用的网络而有助于活化。获得的结果与现有的实验动力学数据一致，并提供了对TLR 286激活机制的原子理解。
Canfosfamide (TLK286, TELCYTA) is a prodrug that upon activation by glutathione transferase P1-1 (GST P1-1) yields an anticancer alkylating agent and a glutathione derivative. The rationale underlying the use of TLK286 in chemotherapy is that tumor cells overexpressing GST P1-1 will be locally exposed to the released alkylating agent with limited collateral toxicity to the surrounding normal tissues. TLK286 has demonstrated clinical effects in phase II and III clinical trials for the treatment of malignancies, such as ovarian cancer, nonsmall cell lung cancer, and breast cancer, as a single agent and in combination with other chemotherapeutic agents. In spite of these promising results, the detailed mechanism of GST P1-1 activation of the prodrug has not been elucidated. Here, we propose a mechanism for the TLK286 activation by GST P1-1 on the basis of density functional theory (DFT) and on potential of mean force (PMF) calculations. A catalytic water molecule is instrumental to the activation by forming a network of intermolecular interactions between the active-site Tyr7 hydroxyl and the sulfone and COO- groups of TLK286. The results obtained are consistent with the available experimental kinetic data and provide an atomistic understanding of the TLK286 activation mechanism.