Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as c-MYC Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction
| Autor: | Zhi-Shu Huang, Lian-Quan Gu, Yu-Qing Wang, Jia-Heng Tan, Chan Shan, Qi-Kun Yin, Chen-Xi Wang, Tian-Miao Ou, Ding Li, Zhou-Li Huang, Shuo-Bin Chen |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell cycle checkpoint Transcription Genetic Down-Regulation Antineoplastic Agents Apoptosis Ligands G-quadruplex Proto-Oncogene Proteins c-myc Structure-Activity Relationship 03 medical and health sciences Transcription (biology) Cell Line Tumor Drug Discovery Animals Humans Pyrroles Promoter Regions Genetic Gene Cell Proliferation Quinazolinones Mice Inbred BALB C Chemistry NM23 Nucleoside Diphosphate Kinases G1 Phase Cell Cycle Checkpoints Xenograft Model Antitumor Assays Molecular biology Small molecule Cell biology G-Quadruplexes Molecular Docking Simulation 030104 developmental biology Design synthesis Doxorubicin Drug Design Quinazolines Molecular Medicine Tumor growth inhibition |
| Zdroj: | Journal of Medicinal Chemistry. 60:6924-6941 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00421 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|