title: Quinazoline derivative QPB-15e stabilizes the c-myc promoter G-quadruplex and inhibits tumor growth in vivo.
abstract: The ribozyme-sensitive element NHE-III1 in the P1 promoter region of the important proto-oncogene c-myc contains many guanine (G)-rich sequences. Induction and stabilization of the G-quadruplex formed by NHE-III1 can downregulate c-myc expression. In the present study, we found that QPB-15e, a quinazoline derivative designed and synthesized by our laboratory, binds to and stabilizes the c-myc G-quadruplex in vitro, thereby inhibiting double-stranded DNA replication, downregulating c-myc gene expression and arresting cancer cell proliferation. PCR termination experiments showed that QPB-15e blocked double-stranded DNA replication by inducing or stabilizing the c-myc G-quadruplex. FRET-melting further confirmed that QPB-15e improved the stability of the G-quadruplex, and CD spectroscopy indicated that the compound interacted directly with the G-rich sequence. In competitive dialysis experiments, QPB-15e bound preferentially to quadruplex DNA in various structures, especially the G-quadruplex within the c-myc promoter region. Moreover, QPB-15e reduced the weights and volumes of tumors transplanted into nude mice. These findings strongly suggest that QPB-15e is a c-myc G-quadruplex ligand with anti-tumor properties, and may be efficacious for treating cancer in humans.
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China.
authors.forename: Zeng
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Meng
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, Guangzhou 510006, China.
authors.forename: Jinhui
authors.initials: J
authors.lastname: He
authors.affiliation: School of Pharmacy, Anhui Medical University, Hefei 230032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D054856:G-Quadruplexes / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects* / Q000235:genetics; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C000715470:MAS1 protein, human; C489427:MYC protein, human; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C000625999:QPB-15e compound; D011799:Quinazolines
keywords: G-quadruplex; QPB-15e; anti-tumor; c-myc; quinazoline derivative