期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 16, 页码 6924-6941出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00421
关键词
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资金
- Natural Science Foundation of China [81330077, 21172272, 21672268, 21472252]
- Guangdong Provincial Science and Technology Development Special Foundation (Public Interest Research and Capacity Building) [2016A020217004]
- Guangdong Provincial Natural Science Foundation for Distinguished Young Scholars [2015A030306004]
- Guangdong Provincial Key Laboratory of Construction Foundation [2011A060901014]
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.
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