title: Chemical intervention of the NM23-H2 transcriptional programme on c-MYC via a novel small molecule.
abstract: c-MYC is an important oncogene that is considered as an effective target for anticancer therapy. Regulation of this gene's transcription is one avenue for c-MYC-targeting drug design. Direct binding to a transcription factor and generating the intervention of a transcriptional programme appears to be an effective way to modulate gene transcription. NM23-H2 is a transcription factor for c-MYC and is proven to be related to the secondary structures in the promoter. Here, we first screened our small-molecule library for NM23-H2 binders and then sifted through the inhibitors that could target and interfere with the interaction process between NM23-H2 and the guanine-rich promoter sequence of c-MYC. As a result, a quinazolone derivative, SYSU-ID-01: , showed a significant interference effect towards NM23-H2 binding to the guanine-rich promoter DNA sequence. Further analyses of the compound-protein interaction and the protein-DNA interaction provided insight into the mode of action for SYSU-ID-01: . Cellular evaluation results showed that SYSU-ID-01: could abrogate NM23-H2 binding to the c-MYC promoter, resulting in downregulation of c-MYC transcription and dramatically suppressed HeLa cell growth. These findings provide a new way of c-MYC transcriptional control through interfering with NM23-H2 binding to guanine-rich promoter sequences by small molecules.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Shan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jin-Qiang
authors.initials: JQ
authors.lastname: Hou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Shuo-Bin
authors.initials: SB
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ai-Chun
authors.initials: AC
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China outianm@mail.sysu.edu.cn.
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China ceshzs@mail.sysu.edu.cn.
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D054778:NM23 Nucleoside Diphosphate Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D054778:NM23 Nucleoside Diphosphate Kinases; D016271:Proto-Oncogene Proteins c-myc; D052999:Quinazolinones; C000602890:SYSU-ID-01; D054852:Small Molecule Libraries; D004247:DNA; C517940:NME2 protein, human