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G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and are over-represented in the promoter regions of many genes involved in human cancer initiation, progression, and metastasis. They are plausible targets for G4-binding small molecules, which would, in the case of promoter G4s, result in the transcriptional downregulation of these genes. However, structural information is currently available on only a very small number of G4s and their ligand complexes. This limitation, coupled with the currently restricted information on the G4-containing genes involved in most complex human cancers, has led to the development of a phenotypic-led approach to G4 ligand drug discovery. This approach was illustrated by the discovery of several generations of tri- and tetra-substituted naphthalene diimide (ND) ligands that were found to show potent growth inhibition in pancreatic cancer cell lines and are active in in vivo models for this hard-to-treat disease. The cycles of discovery have culminated in a highly potent tetra-substituted ND derivative, QN-302, which is currently being evaluated in a Phase 1 clinical trial. The major genes whose expression has been down-regulated by QN-302 are presented here: all contain G4 propensity and have been found to be up-regulated in human pancreatic cancer. Some of these genes are also upregulated in other human cancers, supporting the hypothesis that QN-302 is a pan-G4 drug of potential utility beyond pancreatic cancer. [ABSTRACT FROM AUTHOR]

DNA requires hydration to maintain its structural integrity. Crystallographic analyses have enabled patterns of water arrangements to be visualized. We survey these water motifs in this review, focusing on left- and right-handed duplex and quadruplex DNAs, together with the i-motif. Common patterns of linear spines of water organization in grooves have been identified and are widely prevalent in right-handed duplexes and quadruplexes. By contrast, a left-handed quadruplex has a distinctive wheel of hydration populating the almost completely circular single groove in this structure. [ABSTRACT FROM AUTHOR]

The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes downregulation of the expression of the S100P gene and the S100P protein in cells and in vivo. This protein is well established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The S100P gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides upstream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that S100P expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of upregulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of S100P expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023), and its ability to downregulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the S100P promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302. [ABSTRACT FROM AUTHOR]

A series of 'reversed amidine' substituted heterocycles were prepared to better understand the molecular basis for recognition of the DNA minor groove by heterocyclic cations. The results reveal that amidine derivatives for targeting the minor groove have the amidine carbon linked to a central heterocyclic system whereas in the reverse orientation an amidine nitrogen provides the link.

The structure of an unprecedented G-quadruplex is analyzed with many unique features and a new folding topology that may be formed by a G-rich sequence in the c-kit promoter in the [K.sup.+] region. The analysis reveals that the scaffold contains a total of four loops containing base-pairing alignments and provides a specific platform for further designing of ligands promoting DNA of c-kit.

X-ray and NMR techniques were used to study the structure and topology of quadruplexes based on repeats of the human telomeric sequence d(TTAGGG). The results reveal that the DNA quadruplex topology is parallel-stranded with external double-chain-reversal propeller loops.

The c-kit transcription initiation site (c-kit21), on the G-strand of the promoter region of the c-kit oncogene, which codes for a tyrosine kinase receptor, forms a mixture of stable, putative quadruplexes under near physiological conditions. The quadruplex-forming sequence provides a high level of sequence conservation across human, mouse, rat and chimpanzee, suggesting conservation of biophysical characteristics.

The crystal structure of the DNA sequence d(G(sub 4)T(sub 3)G(sub 4) was determined at 1.5 Lambda resolution, together with that of the brominated analogue d(G(sub 4)(super Br)UTTG(sub 4) at 2.4 Lambda resolution, to assess the effects of a three-nucleotide TTT linker. The presence of three quadruplexes in the P2(sub 1) d(G(sub 4)(super Br)UTTG(sub 4) crystal asymmetric unit provides six independent loop conformation, each in a different crystal-packing environment.

Studies of quadruplex DNA recognition by an engineered Cys2-His2 zinc finger protein (Gq1) reveal that any one finger of Gq1 can be replaced with the corresponding finger of the murine transcription factor Zif268 without significant loss of quadruplex affinity or quadruplex versus duplex discrimination. Replacement of two fingers of Gq1 by Zif268 results in significant impairment of quadruplex recognition and loss of discrimination, which suggests that Zif268-quadruplex binding is weaker.

A study was conducted to understand the shape similar to minor groove-binding compounds DB921 and DB911, which are benzimidazole-biphenyl isomers with terminal charged amidines. The result support minor groove binding for both compounds but do not provide an explanation for the binding of DB921, and DB921 water pair forms a curved binding module that matches the shape of the minor groove and provide a number of strong interactions that are not possible with DB911.

Author(s): Gary N. Parkinson; Michael P. H. Lee; Stephen Neidle (corresponding author) Telomeric ends of chromosomes, which comprise noncoding repeat sequences of guanine-rich DNA, are fundamental in protecting the cell [...]

Research has been conducted on the Bloom's and Werner's syndrome gene products, the members of the RecQ family of DNA helicases. The inhibitory effect of the di- and trisubstituted acridines on the human Bloom's and Werner's syndrome helicases has been investigated and the results are reported.

Results indicate that the ligand BSU1071 either intercalates within a set of four guanine quartets or stacked externally to the quartets of the four strand template sequence of d(TGGGGT). Data demonstrate that the structure of the quadruplex complex is best described with an externally bound ligand complex model.