Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Down-Regulation
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Doxorubicin / pharmacology
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Drug Design
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G-Quadruplexes*
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G1 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Ligands
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Mice, Inbred BALB C
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Molecular Docking Simulation
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NM23 Nucleoside Diphosphate Kinases / antagonists & inhibitors*
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NM23 Nucleoside Diphosphate Kinases / chemistry
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NM23 Nucleoside Diphosphate Kinases / genetics
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors*
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Proto-Oncogene Proteins c-myc / genetics
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Pyrroles / administration & dosage
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Quinazolines / administration & dosage
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Quinazolines / chemical synthesis
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Quinazolines / chemistry
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Quinazolines / pharmacology*
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Quinazolinones / administration & dosage
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Quinazolinones / chemical synthesis
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Quinazolinones / chemistry
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Quinazolinones / pharmacology*
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Structure-Activity Relationship
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Transcription, Genetic
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Xenograft Model Antitumor Assays
Substances
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3-(4-(benzyloxy)-2-hydroxybenzylidene)-6-((3-(dimethylamino)propyl)amino)-7-fluoro-2,3-dihydropyrrolo(2,1-b)quinazolin-9(1H)-one
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Antineoplastic Agents
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Ligands
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MYC protein, human
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NM23 Nucleoside Diphosphate Kinases
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Proto-Oncogene Proteins c-myc
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Pyrroles
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Quinazolines
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Quinazolinones
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Doxorubicin
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NME2 protein, human