Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as c-MYC Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction.
Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as c-MYC Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction.
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DOI：
10.1021/acs.jmedchem.7b00421
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发表时间：
2017-08
影响因子：
7.3
通讯作者：
Yu-Qing Wang;Zhou-Li Huang;Shuo-Bin Chen;Chen-Xi Wang;Chan Shan;Qi-Kun Yin;Tian-Miao Ou;Ding Li-
中科院分区：
文献类型：
--
作者：
Yu-Qing Wang;Zhou-Li Huang;Shuo-Bin Chen;Chen-Xi Wang;Chan Shan;Qi-Kun Yin;Tian-Miao Ou;Ding Li-
c-MYC基因是人类重要的原癌基因之一，转录因子NM 23-H2通过识别c-MYC基因启动子中的G-四链体而激活c-MYC基因的转录。通过破坏NM 23-H2/G-quadruplex相互作用来抑制c-MYC转录的小分子可能是开发选择性抗癌剂的有前途的策略。在最近的研究中，我们开发了一系列靛地内酯衍生物，其可以结合G-四链体和NM 23-H2，从而下调c-MYC（J. Med. Chem. 2017，60，1292 - 1308）。本文设计、合成并筛选了一系列具有选择性结合NM 23-H2配体的新型靛地内酯衍生物。其中，化合物37与NM 23-H2具有很高的特异性结合能力，能有效阻断NM 23-H2与G-四链体的相互作用，并能显著下调c-MYC的转录。此外，37诱导细胞周期停滞和凋亡，并且在小鼠异种移植模型中表现出良好的肿瘤生长抑制。这项工作为开发选择性抗癌药物提供了调控c-MYC转录的新策略。
c-MYC is one of the important human proto-oncogenes, and transcriptional factor NM23-H2 can activate c-MYC transcription by recognizing the G-quadruplex in the promoter of the gene. Small molecules that inhibit c-MYC transcription by disrupting the NM23-H2/G-quadruplex interaction might be a promising strategy for developing selective anticancer agents. In recent studies, we developed a series of isaindigotone derivatives, which can bind to G-quadruplex and NM23-H2, thus down-regulating c-MYC ( J. Med. Chem. 2017 , 60 , 1292 - 1308 ). Herein, a series of novel isaindigotone derivatives were designed, synthesized, and screened for NM23-H2 selective binding ligands. Among them, compound 37 showed a high specific binding affinity to NM23-H2, effectively disrupting the interaction of NM23-H2 with G-quadruplex, and it strongly down-regulated c-MYC transcription. Furthermore, 37 induced cell cycle arrest and apoptosis, and it exhibited good tumor growth inhibition in a mouse xenograft model. This work provides a new strategy to modulate c-MYC transcription for the development of selective anticancer drugs.