Research Papers:
Quinazoline derivative QPB15e stabilizes the cmyc promoter Gquadruplex and inhibits tumor growth in vivo
PDF | Full Text | How to cite
Metrics: PDF 2671 views | Full Text 4702 views
Zeng Li1, Chen Liu1, Cheng Huang1, Xiaoming Meng1, Lei Zhang1, Jinhui He2, Jun Li1
1School of Pharmacy, Anhui Medical University, Hefei 230032, China
2School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, Guangzhou 510006, China
Correspondence to:
Jun Li, email: [email protected]
Keywords: c-myc, G-quadruplex, quinazoline derivative, QPB-15e, anti-tumor
Received: March 06, 2016 Accepted: April 16, 2016 Published: April 28, 2016
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.