Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy

Abstract

A G-quadruplex (G4) is a well-known nucleic acid secondary structure comprising guanine-rich sequences, and has profound implications for various pharmacological and biological events, including cancers. Therefore, ligands interacting with G4s have attracted great attention as potential anticancer therapies or in molecular probe applications. To date, a large variety of DNA/RNA G4 ligands have been developed by a number of laboratories. As protein-targeting drugs face similar situations, G-quadruplex-interacting drugs displayed low selectivity to the targeted G-quadruplex structure. This low selectivity could cause unexpected effects that are usually reasons to halt the drug development process. In this review, we address the recent research on synthetic G4 DNA-interacting ligands that allow targeting of selected G4s as an approach toward the discovery of highly effective anticancer drugs.

Keywords: G-quadruplex; cancer therapy; oncogenes; selective ligands; telomere.

Figure 1

(a) Structure and schematic illustration of a G-tetrad. (b) Schematic illustrations of typical intramolecular G-quadruplex (G4) structures: (left) crystal structure of parallel type telomere G4 (PDB code: 1kf1); (center) solution structure of antiparallel type telomere G4 (PDB code: 143d); (right) solution structure of hybrid type telomere G4 (PDB code: 2gku). The figures were adapted with permission from Reference 56. PDB; Protein Data Bank.

Figure 2

Selective telomere G4 targeting by ligands. (a) Telomere G-stretch sequences potentially adopt non-canonical G4s that offer specific binding motifs. (b) Several telomere G4-preferred binders based on the specific-motif recognition. It is worth noting that the by Ni-M and IZNP1 exhibit differential antitumor activities, likely based on the specific-motif recognition of telomere G4s. (c) EPI and the solution structure of the EPI-wtTel26 complex (PDB code: 6ccw). The bases that do not participate in the interaction event with EPI are omitted for clarity. Figure 2a,c were adapted with permission from References 56 and 86, respectively.

Figure 3

(a) The c-MYC promoter has one putative G4-forming sequence (PQS). (b) Molecules preferentially interacting with its G4 DNAs over other ones. N-Methylpyrrole is highlighted in blue and N-methylimidazole is highlighted in red. Antitumor activities of TH3, IZCZ-3, benzofuran derivative, and Tz 1 are summarized in Table 1.

Figure 4

(a) The VEGF promoter has one putative G4-forming sequence (PQS) located close to the transcription start site (TSS) and hormone response element (HRE) that regulate the transcription. (b) Molecules interacting with its G4 DNAs and efficiently suppressing VEGF protein expression. It is worth noting that SYUIQ-FM05 has potential to reduce VEGF-stimulated tumor angiogenesis.

Figure 5

(a) The BCL2 promoter has two G4-forming elements that were shown to attenuate the BCL2 promoter activity. (b) Molecules preferentially interacting with the G4 (distal one) over other G4 structures. An antitumor activity of furopyridazinone derivative is summarized in Table 1.

Figure 6

(a) The c-kit promoter has two PQSs, where several transcription factors are likely involved. (b) Molecules interacting with its G4 DNA and showing the downregulation of the c-kit gene transcription.

Figure 7

(a) The hTERT promoter has several PQSs, where two tandemly aligned G4s are suggested, and a molecule interacting with the specific motif of its G4 DNA and showing the downregulation of the hTERT gene transcription. The arrows with asterisks in the right illustration of the (b) represent bases that are protected in the presence of GTC365 from methylation by dimethyl sulfate (DMS) in the experiment performed in Reference 102. The protection suggests the occupied site of GTC365. The numbers represent the order of the runs of poly G observed in the hTERT promoter, which are numbered in Reference 102. The antitumor activity of GTC365 is summarized in Table 1. The right illustration of the Figure 7 (b) was adapted with permission from Reference. 172.

Figure 8

(a) The human KRAS promoter has three PQSs. In particular, the G4 formation at the most proximal PQS (PQS1) is shown to act as a stronger transcriptional repressor. (b) Molecules interacting with its G4 DNA and causing antitumor activities.

Figure 9

(a) The c-myb promoter has multiple PQSs. (b) A molecule interacting with its G4 DNA and efficiently repressing MYB protein expression.

Figure 10

(a–c) G-triplex-targeting ligands. (c) A platform for their evaluation constructed by DNA origami.

Figure 11

Head-to-head polyamide dimer that can target a certain G4 by simultaneously binding to dual-duplex sites across the G4. N-Methylpyrrole is highlighted in blue, and N-methylimidazole is highlighted in red.