Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as c-MYC Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction
- 4 August 2017
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 60 (16), 6924-6941
- https://doi.org/10.1021/acs.jmedchem.7b00421
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.Keywords
Funding Information
- National Natural Science Foundation of China (21172272, 21472252, 21672268, 81330077)
- Natural Science Foundation of Guangdong Province (2015A030306004)
- Guangdong Provincial Key Laboratory of Construction Foundation, Sun Yat-sen University (2011A060901014)
- Science and Technology Development Special Foundation of Guangdong Province (2016A020217004)
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