Recent Advances in Anticancer Drugs Development: G-Quadruplex as New Drug Target

Abstract

Nucleic Acids are large biomolecules and indispensable for life. They include deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic acids can adopt distinct non-canonical, highly compact secondary structure, G-quadruplex, in the dynamic region of chromosomal DNA and RNA transcripts, predominantly in telomeric sequences, and in promoter region of numerous genes including oncogenes such as Bcl-2 [1,2], VEGF [3,4], c-myc [5]. There are 376,000 putative quadruplex sequences (PQS) in the human genome that have been identified through genome-wide surveys based on a quadruplex folding rule [6], however, all of them may not exist in vivo. Recently, the existence of DNA G-quadruplex has been visualized on chromosomes in human cells [7]. These G-quadruplexes are an active target of drug discovery. The DNA G-quadruplexes formed in the promoter region of oncogene have been shown to be potential targets for anticancer drugs [8,9] and proteins. The formation of these quadruplexes in telomeres has been shown to regulate the activity of the enzyme telomerase, which maintains the length of telomeres and is involved in ~85% of all cancers. For example, Telomestatin [10,11], S2T1-6OTD (telomestatin synthetic Derivative) [12], SYUIQ-5 [13] interact with G-quadruplex formed in telomere and myc sequences and show their inhibitory activity in cancer cell growth. This has become a progressively large field of research. The G-quadruplexes are very condensed structures and formed by the ganosine (G)-rich DNA and RNA sequences and consists of several stacked G-tetrads. Each G-tetrad has four guanine arranged in a square planar arrangement and held together by hoogsteen hydrogen bonding. Besides this, each G-quadruplex structure is further stabilized by the presence of a monovalent cation, mainly potassium, which is localized in the center between each pair of tetrads. The G-quadruplexes could affect gene activity either by upregulation or down regulation, which can be achieved by inducing or stabilizing G-quadruplex formation through a G-quadruplex interacting molecule (small molecule drugs or protein) that can stabilize the G-quadruplex structure and thus perform their desired function [8]. The validation of drug-targeted G-quadruplex DNA and the modulation of cancer genes’ expression has been intensely increased in the recent past, thus opening new avenue for cancer research. Though a lot of research has been focused on DNA G-quadruplexes, there has lately been a rapid advancement in the area of RNA G-quadruplexes, chiefly in the 5 ′-UTRs (untranslated regions) of mRNAs. RNA G-quadruplexes in the 5’-UTRs of mRNAs impact posttranscriptional regulation of gene expression, which affects disruption of normal cell behavior in human diseases, particularly cancers. The recent in-vitro study on small molecule G-quadruplex binding compound that can selectively target RNA G-quadruplexes exposed a new and striking opportunity for RNA-directed drug design [14]. However, there is still a major challenge to understand the systematic effects and selectivity in in-vivo environment. It is distinct that the RNA G-quadruplex motif embodies a structurally attractive scaffold for small molecule targeting and therefore provides a productive area for future research [15].