Quinazoline derivative QPB-15e stabilizes the c-myc promoter G-quadruplex and inhibits tumor growth in vivo.
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.
['Li|Zeng|Z|', 'Liu|Chen|C|', 'Huang|Cheng|C|', 'Meng|Xiaoming|X|', 'Zhang|Lei|L|', 'He|Jinhui|J|', 'Li|Jun|J|']
D000818:Animals D000970:Antineoplastic Agents D001549:Benzamides D045744:Cell Line, Tumor D054856:G-Quadruplexes D016259:Genes, myc D006801:Humans D051379:Mice D008807:Mice, Inbred BALB C D008819:Mice, Nude D009374:Neoplasms, Experimental D011401:Promoter Regions, Genetic D000090063:Proto-Oncogene Mas D016271:Proto-Oncogene Proteins c-myc D011799:Quinazolines D023041:Xenograft Model Antitumor Assays
quinazoline derivative QPB-15e c-myc G-quadruplex anti-tumor