Purpose: Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released. 3′-Deoxyadenosine (3′-dA) is a naturally occurring adenosine analogue with established anticancer activity in vitro but limited bioavailability due to its rapid in vivo deamination by the circulating enzyme adenosine deaminase, poor uptake into cells, and reliance on adenosine kinase for its activation. In order to overcome these limitations, 3′-dA was chemically modified to create the novel ProTide NUC-7738. Experimental Design: We describe the synthesis of NUC-7738. We determine the IC50 of NUC-7738 using pharmacokinetics (PK) and conduct genome-wide analyses to identify its mechanism of action using different cancer model systems. We validate these findings in patients with cancer. Results: We show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3′-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide-binding protein 1. PK and tumor samples obtained from the ongoing first-in-human phase I clinical trial of NUC-7738 further validate our in vitro findings and show NUC-7738 is an effective proapoptotic agent in cancer cells with effects on the NF-κB pathway. Conclusions: Our study provides proof that NUC-7738 overcomes cellular resistance mechanisms and supports its further clinical evaluation as a novel cancer treatment within the growing pantheon of anticancer ProTides. This article is featured in Highlights of This Issue, [p. 6279][1] [1]: /lookup/volpage/27/6279?iss=23

中文翻译：

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新型核苷类似物 ProTide NUC-7738 在体外和首次人体 I 期临床试验中克服了癌症耐药机制


目的：核苷类似物构成了肿瘤学中许多治疗方案的支柱，并且需要细胞内酶的存在才能激活它们。 ProTide 由与保护性氨基磷酸帽融合的核苷组成。 ProTides 很容易掺入细胞中，从而裂解帽并释放预激活的核苷。 3'-脱氧腺苷 (3'-dA) 是一种天然存在的腺苷类似物，具有体外抗癌活性，但由于其在体内被循环酶腺苷脱氨酶快速脱氨、细胞摄取差以及依赖腺苷激酶，其生物利​​用度有限。它的激活。为了克服这些限制，对 3'-dA 进行了化学修饰，创建了新型 ProTide NUC-7738。实验设计：我们描述了 NUC-7738 的合成。我们使用药代动力学 (PK) 确定 NUC-7738 的 IC50，并使用不同的癌症模型系统进行全基因组分析，以确定其作用机制。我们在癌症患者中验证了这些发现。结果：我们表明 NUC-7738 克服了限制 3'-dA 活性的抗癌机制，并且其激活依赖于组氨酸三联体核苷酸结合蛋白 1 酶对 ProTide 的裂解。从正在进行的研究中获得的 PK 和肿瘤样本NUC-7738 的首次人体 I 期临床试验进一步验证了我们的体外研究结果，并表明 NUC-7738 是癌细胞中的一种有效促凋亡剂，对 NF-κB 通路有影响。结论：我们的研究证明 NUC-7738 克服了细胞耐药机制，并支持其作为不断增长的抗癌 ProTides 中的一种新型癌症治疗方法进行进一步的临床评估。本文收录于本期亮点，[p. 11]。 6279][1][1]：/lookup/volpage/27/6279？国际空间站=23