Trisubstituted Isoalloxazines as a New Class of G-Quadruplex Binding Ligands: Small Molecule Regulation of c-kit Oncogene Expression

摘要

Particular guanine rich DNA sequences can fold into stable four-stranded G-quadruplex structures, under physiological concentrations of Na~+ and K~+, in vitro. Such sequence motifs are found in the telomeres where they can fold into quadruplexes under the control of specific telomere binding proteins. G-quadruplex motifs have been identified throughout the genome and concentrate immediately upstream of transcription initiation sites. A number of these so-called "promoter quadruplex" sequences have been studied for several proto-oncogenes, including c-MYC, BCL2, VEGF, KRAS and two G-quadruplexes in the c-kit promoter (c-kit1 and c-kit2). One working hypothesis couples quadruplex formation in promoters to transcription, suggesting an opportunity for chemical intervention of gene expression using small molecule G-quadruplex ligands. Some proof-of-concept has been provided for the case of c-MYC where small molecule ligands, TmPyP4, and quindoline derivatives have been shown to inhibit gene expression, while KRAS gene expression was inhibited by TmPyP4.