Targeting the KRAS oncogene: Synthesis, physicochemical and biological evaluation of novel G-Quadruplex DNA binders

D’Aria, Federica; D’Amore, Vincenzo Maria; Leva, Francesco Saverio Di; Amato, Jussara; Caterino, Marco; Russomanno, Pasquale; Salerno, Silvia; Barresi, Elisabetta; Leo, Marinella De; Marini, Anna María; Taliani, Sabrina; Settimo, Federico Da; Salgado, Gilmar F.; Pompili, Luca; Zizza, Pasquale; Shirasawa, Senji; Novellino, Ettore; Biroccio, Annamaria; Marinelli, Luciana; Giancola, Concetta

doi:10.1016/j.ejps.2020.105337

Cited by 21 publications

(25 citation statements)

References 88 publications

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“…CD experiments were carried out to study the conformational properties and thermal stability of the G4 structures of the here studied MS3 analogues [ 53 ]. In both selected buffer solutions, CD spectra of MS3-33 and MS3-17, collected at 5 °C, showed the characteristic profile of a predominantly parallel G4 folding, with a maximum at 263 nm and a minimum at 240 nm ( Figure 2 ) [ 54 , 55 ]. The positive CD bands showed higher intensities in PBS than in the Na + buffer, suggesting a higher structuration degree in PBS, in line with the higher stability of G4s in K + -containing solutions [ 46 , 47 , 48 ].…”

Section: Resultsmentioning

confidence: 99%

Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

Riccardi

D’Aria

Fasano

et al. 2022

IJMS

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Two analogues of the MS3 aptamer, which was previously shown to have an exquisite capability to selectively bind and modulate the activity of mutant huntingtin (mHTT), have been here designed and evaluated in their physicochemical and biological properties. Featured by a distinctive propensity to form complex G-quadruplex structures, including large multimeric aggregates, the original 36-mer MS3 has been truncated to give a 33-mer (here named MS3-33) and a 17-mer (here named MS3-17). A combined use of different techniques (UV, CD, DSC, gel electrophoresis) allowed a detailed physicochemical characterization of these novel G-quadruplex-forming aptamers, tested in vitro on SH-SY5Y cells and in vivo on a Drosophila Huntington’s disease model, in which these shorter MS3-derived oligonucleotides proved to have improved bioactivity in comparison with the parent aptamer.

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Section: Resultsmentioning

confidence: 99%

Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

Riccardi

D’Aria

Fasano

et al. 2022

IJMS

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“…A new chemotype, compound 19, displayed a high affinity for k-RAS G4, with a 1:1 stoichiometry ratio and a remarkable selectivity against duplex DNA. It was also shown to inhibit the transcription of the k-RAS driver oncogene which had been long considered undruggable [58].…”

Section: Selective G4 Ligandsmentioning

confidence: 99%

Quadruplex Ligands in Cancer Therapy

Sánchez-Martín

Soriano

García‐Salcedo

2021

Cancers

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Nucleic acids can adopt alternative secondary conformations including four-stranded structures known as quadruplexes. To date, quadruplexes have been demonstrated to exist both in human chromatin DNA and RNA. In particular, quadruplexes are found in guanine-rich sequences constituting G-quadruplexes, and in cytosine-rich sequences forming i-Motifs as a counterpart. Quadruplexes are associated with key biological processes ranging from transcription and translation of several oncogenes and tumor suppressors to telomeres maintenance and genome instability. In this context, quadruplexes have prompted investigations on their possible role in cancer biology and the evaluation of small-molecule ligands as potential therapeutic agents. This review aims to provide an updated close-up view of the literature on quadruplex ligands in cancer therapy, by grouping together ligands for DNA and RNA G-quadruplexes and DNA i-Motifs.

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“…Accumulating evidence revealed the potential anti-tumor activity of small molecules targeting KRAS G-quadruplex DNA molecules. For example, natural products [ 29 ], porphyrin derivatives [ 30 ], quinoline derivatives [ 31 ], and aromatic compounds [ 32 ] are considered promising KRAS G-quadruplex stabilizers. A major research breakthrough has been achieved using a small molecule AMG 510 as a potential mutant KRAS (G12C) inhibitor with high specificity and sensitivity to effectively block tumor growth in vivo [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

Arene Ru(II) Complexes Acted as Potential KRAS G-Quadruplex DNA Stabilizer Induced DNA Damage Mediated Apoptosis to Inhibit Breast Cancer Progress

Qian

Liu

et al. 2022

Molecules

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A series of arene Ru(II) complexes, [(η6-MeC6H5)Ru(L)Cl]Cl, (L=o-ClPIP, 1; m-ClPIP, 2 and p-ClPIP, 3) (o-ClPIP=2-(2-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline; m-ClPIP=2-(3-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline; p-ClPIP=2-(4-chlorophenyl)imidazo[4,5-f][1,10]phenanthroline) was synthesized and investigated as a potential apoptosis inducer in chemotherapy. Spectroscopy and molecular docking simulations show that 1 exhibits moderated binding affinity to KRAS G-quadruplex DNA by groove mode. Further, in vitro studies reveal that 1 displays inhibitory activity against MCF-7 growth with IC50 = 3.7 ± 0.2 μM. Flow cytometric analysis, comet assay, and immunofluorescence confirm that 1 can induce the apoptosis of MCF-7 cells and G0/G1 phase arrest through DNA damage. In summary, the prepared arene Ru(II) complexes can be developed as a promising candidate for targeting G-quadruplex structure to induce the apoptosis of breast cancer cells via binding and stabilizing KRAS G-quadruplex conformation on oncogene promoter.

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Targeting the KRAS oncogene: Synthesis, physicochemical and biological evaluation of novel G-Quadruplex DNA binders

Cited by 21 publications

References 88 publications

Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

Truncated Analogues of a G-Quadruplex-Forming Aptamer Targeting Mutant Huntingtin: Shorter Is Better!

Quadruplex Ligands in Cancer Therapy

Arene Ru(II) Complexes Acted as Potential KRAS G-Quadruplex DNA Stabilizer Induced DNA Damage Mediated Apoptosis to Inhibit Breast Cancer Progress

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