Discovery of novel functionalized 1,2,4-triazoles as PARP-1 inhibitors in breast cancer: Design, synthesis and antitumor activity evaluation
Discovery of novel functionalized 1,2,4-triazoles as PARP-1 inhibitors in breast cancer: Design, synthesis and antitumor activity evaluation
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DOI：
10.1016/j.ejmech.2019.111621
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发表时间：
2019-11-15
影响因子：
6.7
通讯作者：
Satta, Sandro
中科院分区：
文献类型：
--
作者：
Boraei, Ahmed T. A.;Singh, Pankaj K.;Satta, Sandro
PARP-1是一种核蛋白，是DNA修复组装的关键成员之一，因此成为抗癌药物发现的一个有吸引力的靶点。PARP-1在BRCA1/ brca2突变乳腺癌的碱基切除修复中起关键作用，是细胞存活的重要途径。在这种情况下，本研究的目标是确定PARP-1抑制剂的新原型，用于开发治疗乳腺癌的抗肿瘤疗法。因此，首先利用内部文库进行了基于结构的药物设计探索，重点是三唑-硫酮和烷基磺胺基-三唑支架。具有良好结合亲和力和较好预测抑制电位的hit也测试了它们的PARP-1抑制活性。此外，对所选化合物进行了体外细胞毒性评价。这种方法鉴定了一些在低微摩尔范围内显示出有趣的抗增殖潜力的新化合物。结果表明，所鉴定的铅分子可能通过干扰PARP-1酶活性有效地阻碍细胞迁移和细胞增殖。版权所有：Elsevier Masson SAS版权所有。
PARP-1, a nuclear protein, is one of the key member of the DNA repair assembly and thereby emerged as an attractive target in anti-cancer drug discovery. PARP-1 plays a key role in terms of base excision repair, which is an important pathway for cell survival in breast cancer with BRCA1/BRCA2-mutation. In this scenario, the goal of this study was to identify novel prototypes of PARP-1 inhibitors for the development of antitumor therapeutics to treat breast cancer. Thus, a structure-based drug design exploration was first conducted using an in-house library, focusing on triazole-thione and alkylsulfanyl-triazole scaffold. Hits with good binding affinity and better predicted inhibitory potential were also tested for their PARP-1 inhibitory activity. Moreover, the selected compounds were evaluated for their cytotoxicity in-vitro. This approach led to the identification of few novel compounds showing interesting anti-proliferative potential in low micromolar range. Results disclosed that the identified lead molecules were efficiently impeding cell migration and cell proliferation, potentially by interfering with PARP-1 enzymatic activities. Crown Copyright (C) 2019 Published by Elsevier Masson SAS. All rights reserved.