Exploring the Interaction of Curaxin CBL0137 with G-Quadruplex DNA Oligomers

Abstract

Curaxins and especially the second-generation derivative curaxin CBL0137 have important antitumor activities in multiple cancers such as glioblastoma, melanoma and others. Although most of the authors suggest that their mechanism of action comes from the activation of p53 and inactivation of NF-kB by targeting FACT, there is evidence supporting the involvement of DNA binding in their antitumor activity. In this work, the DNA binding properties of curaxin CBL0137 with model quadruplex DNA oligomers were studied by 1H NMR, CD, fluorescence and molecular modeling. We provided molecular details of the interaction of curaxin with two G-quadruplex structures, the single repeat of human telomere d(TTAGGGT)4 and the c-myc promoter Pu22 sequence. We also performed 1H and 31P NMR experiments were also performed in order to investigate the interaction with duplex DNA models. Our data support the hypothesis that the interaction of curaxin with G-quadruplex may provide a novel insight into the DNA-binding properties of CBL0137, and it will be helpful for the design of novel selective DNA-targeting curaxin analogues.

Parallel DNA G-Quadruplex Induced and Stabilized by Curaxin CBL0137

“…The increase in loop length results in an increase in the proportion of unfolded G4 molecules, while the addition of CBL0137 promotes and stabilizes the folding of G4. Compared with the ensembleaverage and static results from NMR that CBL0137 interacts with G4 in both telomeres and oncogene promoter regions, [18] our study directly illustrates the folding dynamics of G4 under the influence of CBL0137, with singlemolecule resolutions. It is known that G4 sequences are present in ∼ 50% of human gene promoters, especially in oncogene promoters [34,35] including c-MYC, [36] VEGF, [37] HIF-1𝛼, [38] and c-KIT.…”

“…Moreover, we note that the proportions of anti-parallel structure for G4L4 and G4L5 with longer loops have not decreased after adding the CBL0137. According to the previous study using NMR and CD methods, [18] the CBL0137 binds to the exposed sides of the two external G-tetrads and stabilizes the G4 structure. Thus one possible explanation for the observed phenomenon is that, while a short loop may partially block the binding of CBL0137 to G4 in the anti-parallel conformation [see Fig.…”

“…[16,17] Recently, the binding between CBL0137 and G4 was revealed by the nuclear magnetic resonance (NMR) method. [18] However, how CBL0137 regulates the structure and property of G4 remains unclear, limiting further applications of curaxin drugs in clinic. In contrast to ensemble-average methods, the single-molecule fluorescence resonance energy transfer (smFRET) technique may track the real-time dynamical behaviors of individual G4 molecules and provide precise information on G4 conformation changes and folding dynamics.…”

Selective Ligands for Non-Canonical DNA Structures: Do They Have a Future in Medicinal Chemistry?

“…Using NMR and modeling techniques, Dallavalle and colleagues [ 11 ] investigated the binding of Curaxins, in particular CBl0137, to non-canonical DNA structures. This was originally not included in the proposed mechanisms of action, but recent findings seem to support G4 binding as well.…”

Exploring the Interaction of G-quadruplex Binders with a (3 + 1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region

“…Recent findings have claimed the involvement of DNA binding in the curaxin antitumor activity [ 23 , 24 ]. The NMR studies by our group evidenced a significant binding of curaxin with the single repeat sequence of human telomeres (TTAGGGT) 4 and with Pu22T14T23, a model of the c-myc promoter Pu22 sequence [ 25 ]. Investigations of BMH21, BA41 and CX-5461 ( Figure 1 ), [ 26 ] provided evidence that these compounds are also effective binders of the human telomeric and oncogene promoter G-quadruplexes, such as c-MYC and c-KYT.…”