Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a DNA repair enzyme that removes 5'-phosphotyrosyl blockages resulting from topoisomerase II (TOP2)-DNA cleavage complexes trapped by TOP2 inhibitors. TDP2 is a logical target for the development of therapeutics to complement existing treatments based on inhibition of TOP2. There is, however, no TDP2 inhibitor in clinical development at present. Of the reported TDP2 inhibitors, the deazaflavins are the most promising chemical class centered around the lead compound SV-5-153. Recently we reported new subtypes derived within the deazaflavin family with improved membrane permeability properties. In this work we characterize two representative analogues from two new deazaflavin subtypes based on their biochemical TDP2 inhibitory potency and drug-likeness. We demonstrate that the ZW-1288 derivative represents a promising direction for the development of deazaflavins as therapeutic agents. ZW-1288 exhibits potent inhibitory activity at low nanomolar concentrations against recombinant and cellular human TDP2 with profile similar to that of the parent analog SV-5-153 based on high resistance against murine TDP2 and human TDP2 mutated at residue L313H. While expressing weak cytotoxicity on its own, ZW-1288 potentiates the clinical TOP2 inhibitors etoposide (ETP) and mitoxantrone in human prostate DU145 and CCRF-CEM leukemia and chicken lymphoma DT40 cells while not impacting the activity of the topoisomerase I (TOP1) inhibitor camptothecin or the PARP inhibitor olaparib. ZW-1288 increases the uptake of ETP to a lesser extent than SV-5-153 and remained active in TDP2 knockout cells indicating that the deazaflavin TDP2 inhibitors have additional cellular effects that will have to be taken into account for their further development as TDP2 inhibitors.

中文翻译：

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新型脱氮黄素酪氨酰-DNA磷酸二酯酶2（TDP2）抑制剂。

酪氨酰-DNA磷酸二酯酶2（TDP2）是一种DNA修复酶，可消除由TOP2抑制剂捕获的拓扑异构酶II（TOP2）-DNA裂解复合物引起的5'-磷酸酪氨酰阻塞。TDP2是开发疗法的逻辑目标，以补充基于抑制TOP2的现有疗法。但是，目前在临床开发中没有TDP2抑制剂。在已报道的TDP2抑制剂中，脱氮黄素类化合物是最有前途的化学类别，主要围绕先导化合物SV-5-153。最近，我们报道了在deazaflavin家族中衍生的具有改善的膜通透性的新亚型。在这项工作中，我们根据其生化TDP2抑制潜能和药物相似性，从两个新的脱氮黄素亚型中表征了两个代表性的类似物。我们证明ZW-1288衍生物代表了脱氮黄素作为治疗剂的发展的有希望的方向。ZW-1288在低纳摩尔浓度下对重组和细胞人TDP2表现出有效的抑制活性，基于对鼠TDP2和残基L313H突变的人TDP2的高抗性，其轮廓与亲本类似物SV-5-153相似。ZW-1288自身表达微弱的细胞毒性时，可增强人前列腺DU145和CCRF-CEM白血病及鸡淋巴瘤DT40细胞中的临床TOP2抑制剂依托泊苷（ETP）和米托蒽醌，同时不影响拓扑异构酶I（TOP1）抑制剂喜树碱的活性或PARP抑制剂olaparib。