Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester M20 4BX, U.K.
J Med Chem. 2013 Aug 22;56(16):6352-70. doi: 10.1021/jm400568p. Epub 2013 Jul 31.
The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.
最近发现的酶酪氨酸-DNA 磷酸二酯酶 2（TDP2）被认为参与了拓扑异构酶介导的 DNA 损伤修复。在临床环境中，有人假设 TDP2 可能通过依托泊苷介导拓扑异构酶 II（topo II）抑制的药物耐药性。因此，选择性地抑制 TDP2 被提议作为一种克服拓扑异构酶靶向药物治疗的固有或获得性耐药的新方法。在高通量筛选（HTS）活动之后，发现 toxoflavins 和 deazaflavins 是该酶的第一个报道的亚微摩尔和选择性抑制剂。Toxoflavin 衍生物似乎对 TDP2 酶抑制表现出明显的构效关系（SAR）。然而，我们观察到该系列的一个关键氧化还原易感性问题，以及早期的体外药物代谢和药代动力学（DMPK）问题，排除了进一步的探索。deazaflavins 是从 HTS 中的一个单一命中物发展而来的。该系列表现出不同的 SAR，并且没有显示出氧化还原活性；然而，低细胞通透性被证明是一个挑战。
