Discovery of Small Molecules for Repressing Cap-Independent Translation of Human Vascular Endothelial Growth Factor (hVEGF) as Novel Antitumor Agents

5 years ago

Discovery of Small Molecules for Repressing Cap-Independent Translation of Human Vascular Endothelial Growth Factor (hVEGF) as Novel Antitumor Agents

Shi-Ke Wang, Jia-Heng Tan, Tian-Miao Ou, Zhi-Shu Huang, Hui-Yun Liu, Shu-Ling Lin, Qi Zhang, Guo-Tao Kuang, Xiao-Qin Wang, Yue Wu

Angiogenesis is important in tumorigenesis and tumor progression. Human vascular endothelial growth factor (hVEGF) is an angiogenic growth factor that plays a crucial role in tumor progression. The G-rich region within the 5′-untranslated regions (5′-UTR) of hVEGF-A mRNA can form a “switchable” RNA G-quadruplex structure that is essential for a cap-independent translation initiation. We screened our small-molecule library for binders of this G-tract. One novel quinazoline derivative, compound 1, showed a significant specific interaction with the G-tract and destabilized the G-quadruplex structure. The results of cellular experiments revealed that compound 1 down-regulated hVEGF-A translation and significantly impeded tumor cells migration. We also found that compound 1 exhibited tumor-inhibiting activity in MCF-7 xenograft tumors, which might be related to its ability to reduce hVEGF expression. These findings present a new strategy of hVEGF-A translational control in which small molecules interact with G-quadruplex structure in the 5′UTR.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.6b01444

DOI: 10.1021/acs.jmedchem.6b01444