Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present.
Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present.
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DOI：
10.3390/biom12060815
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发表时间：
2022-06-10
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
核糖核苷酸还原酶（RR）是所有生物体内必需的多亚基酶；它催化了dNTP合成中的限速步骤，即二磷酸核糖核苷转化为脱氧核糖核苷二磷酸。由于人类RR （hRR）在细胞复制过程中的表达水平很高，hRR一直被认为是包括癌症在内的一系列增殖性疾病的有吸引力的药物靶点。虽然关于hRR的结构、功能和临床重要性有许多优秀的综述，但近年来，抑制hRR的新方法有所增加，值得对现有抑制剂和靶向该酶的策略进行更新的讨论。在这篇综述中，我们讨论了hRRM1（大催化亚基）的经典核苷类似物抑制剂，包括吉西他滨和氯法拉滨，以及hRRM2（自由基小亚基）的抑制剂，包括triap平和羟基脲的机制和临床应用。此外，我们还讨论了靶向RR的新方法和新类型hRR抑制剂的发现。
Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme. In this review, we discuss the mechanisms and clinical applications of classic nucleoside analog inhibitors of hRRM1 (large catalytic subunit), including gemcitabine and clofarabine, as well as inhibitors of the hRRM2 (free radical housing small subunit), including triapine and hydroxyurea. Additionally, we discuss novel approaches to targeting RR and the discovery of new classes of hRR inhibitors.
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影响因子：
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