Biology subjects

Hudson, R. H. E.

Publications and source records attributed to Hudson, R. H. E..

3 recordsLinked to original sources

bioRxiv2026

The DNA damaging properties of the experimental G-quadruplex (G4) drug QN-302 are potentiated by the DNA repair inhibitor Olaparib and mitigated by the molecular helicase PhpC

BackgroundQN-302 is a tetra-substituted naphthalene diimide (NDI) compound designed to interact with G-quadruplex (G4) DNA. QN-302 is currently being evaluated in a phase 1 clinical trial on patients with advanced pancreatic ductal adenocarcinoma (PDAC) and other solid tumors. However, the mechanistic origin(s) of its anticancer activity remains to be fully understood. ResultsWe report herein the ability of QN-302 to damage DNA at G4 sites in cancer cells. To this end, we implemented a series of in vitro assays (FQA and FRET-melting) and cell-based techniques (in situ click imaging and immunodetection) that concurred in demonstrating both the DNA damaging properties of QN-302 and its ability to engage G4s in human cancer cells. Then, we investigate its anticancer effects in PDAC (MIA PaCa-2 cells) and show that it can be efficiently potentiated upon combination with Olaparib, an inhibitor of DNA repair, in an approach referred to as chemically induced synthetic lethality. ConclusionThis study not only confirms the excellent anticancer properties of QN-302 in human cancer cells but also provides insights into its mechanism of action. The optimization of this therapeutic activity by combination with Olaparib opens a promising new avenue for improving its clinical efficacy.

cancer biology↗

bioRxiv2024

Small-molecule-based regulation of gene expression in human astrocytes upon both positive and negative actuations of G-quadruplex control systems

A great deal of attention is currently being paid to strategies aiming at uncovering the biology of the four-stranded nucleic acid structure G-quadruplex (G4) via their stabilization in cells using G4-specific ligands. The conventional definition of chemical biology implies that a complete assessment of G4 biology can only be achieved through the implementation of a complementary approach involving the destabilization of cellular G4s by ad hoc molecular effectors. We report here on an unprecedented comparison of the cellular consequences of G4 chemical stabilization by pyridostatin (PDS) and destabilization by phenylpyrrolocytosine (PhpC) at both transcriptome- and proteome-wide scales in patient-derived human brain cells. Our results show that the stabilization of G4s by PDS triggers the dysregulation of many cellular circuitries, the most drastic effects originating in the downregulation of 354 transcripts and 158 proteins primarily involved in RNA transactions. In contrast, the destabilization of G4s by PhpC modulates the G4 landscapes in a far more focused manner with the upregulation of 295 proteins mostly involved in RNA transactions as well, thus mirroring the effects of PDS. Our study is the first of its kind to report on the extent of G4-associated cellular circuitries in human cells by systematically pitting the effect of G4 stabilization against destabilization in a direct and unbiased manner.

genetics↗

bioRxiv2020

Disclosing the actual efficiency of G-quadruplex DNA-disrupting small molecules

The quest for small molecules that avidly bind to G-quadruplex-DNA (G4-DNA, or G4), so called G4-ligands, has invigorated the G4 research field from its very inception. Massive efforts have been invested to i- screen or design G4-ligands, ii- evaluate their G4-interacting properties in vitro through a series of now widely accepted and routinely implemented assays, and iii- use them as unique chemical biology tools to interrogate cellular networks that might involve G4s. In sharp contrast, only uncoordinated efforts at developing small molecules aimed at destabilizing G4s have been invested to date, even though it is now recognized that such molecular tools would have tremendous application to neurobiology as many genetic and age-related diseases are caused by an over-representation of G4s, itself caused by a deficiency of G4-resolving enzymes, the G4-helicases. Herein, we report on our double effort to i- develop a reliable in vitro assay to identify molecules able to destabilize G4s, the G4-unfold assay, and ii- fully characterize the first prototype of G4-disrupting small molecule, a phenylpyrrolcytosine (PhpC)-based G-clamp analog.

biophysics↗