Quinazoline derivative QPB-15e stabilizes the c-myc promoter G-quadruplex and inhibits tumor growth in vivo

// Zeng Li 1 , Chen Liu 1 , Cheng Huang 1 , Xiaoming Meng 1 , Lei Zhang 1 , Jinhui He 2 , Jun Li 1 1 School of Pharmacy, Anhui Medical University, Hefei 230032, China 2 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou University City, Guangzhou 510006, China Correspondence to: Jun Li, email: jl3849@sohu.com 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.