Programmable oligomers targeting 5′-GGGG-3′ in the minor groove of DNA and NF-κB binding inhibition

Chenoweth, David M.; Poposki, Julie A.; Marques, Michael A.; Dervan, Peter B.

doi:10.1016/j.bmc.2006.10.051

Cited by 21 publications

(13 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most likely, given its potent activity in our reporter assays, this compound targets MMP-9 transcription. Indeed, because of structural similarity to purine bases, it might be that the benzimidazole ring binds the minor groove of DNA to regulate transcription (Briehn et al, 2003;Chenoweth et al, 2007). However, we found no evidence that MPBD affects DNA-protein complex formation at the MMP-9 AP-1 motif, whereas such a mechanism would not explain how the transactivation activity of the Gal4-c-Jun fusion protein is repressed either.…”

Section: Downloaded Fromcontrasting

confidence: 53%

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

Nair

Ávila

et al. 2007

Mol Pharmacol

View full text Add to dashboard Cite

Aberrant gene expression is one of the driving forces for cancer progression and is considered an ideal target for chemical intervention. Although emerging bioluminescence reporter systems allow high-throughput searches for small molecules regulatory for gene expression, frequent silencing of reporter genes by epigenetic mechanisms hinders wide application of this drug discovery strategy. Here we report a novel system that directs the integration of a promoter-reporter construct to an open chromosomal location by Flp-mediated homologous recombination, thereby overcoming reporter-gene silencing. Using this system, we have screened more than 8000 compounds in the DIVERSet chemical library for repressors of a matrix metalloproteinase-9 (MMP-9) promoter and identified 5-methyl-2-(4-methylphenyl)-1H-benzimidazole (MPBD) inhibitory for MMP-9 gene expression. Consistent with this effect, MPBD inhibits MMP-9-dependent invasion of UMSCC-1 oral cancer cells, preosteoclast migration, and receptor activator of nuclear factor-B ligand-induced osteoclast activity over concentration ranges that repressed MMP-9 expression. Mechanistic studies indicated that MPBD antagonizes AP-1 function by inhibiting its transactivation activity. We conclude that the Flp-mediated homologous recombination system to direct reporter integration into open chromatin regions represents a novel strategy allowing for the development of high-throughput systems screening for lead compounds targeting aberrant gene expression in cancer.

show abstract

Section: Downloaded Fromcontrasting

confidence: 53%

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

Nair

Ávila

et al. 2007

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…The amide-hydrocycle unit hasa lso been replaced with BI or azaBI to recognize A·TorG ·Cb ps. [4,[41][42][43][44] Our understanding of G·Cb pr ecognition by small molecule, minorgroove binders remains very limited, however,a nd additional molecular structures are needed to not only expand the use of the DNA as ac ellular drug receptor but also the compound uptake potentialind ifferent organismsand cell types.…”

Section: Compounds:design Conceptsmentioning

confidence: 99%

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

Guo

Kumar

Farahat

et al. 2016

Chemistry A European J

View full text Add to dashboard Cite

In spite of its importance in cell function, targeting DNA is under-represented in the design of small molecules. A barrier to progress in this area is the lack of a variety of modules that recognize G•C base pairs (bp) in DNA sequences. To overcome this barrier an entirely new design concept for modules that can bind to mixed GC and AT sequences of DNA is reported. Because of their successes in biological applications, minor-groove-binding heterocyclic cations were selected as the platform for design. Binding to AT sequences requires H-bond donors while recognition of the G-NH2 requires an acceptor. The concept that we report here uses preorganized N-methylbenzimidazole (N-MeBI) thiophene modules for selective binding with mixed bp DNA sequences. The interaction between the thiophene sigma-hole (positive electrostatic potential) and electron donor nitrogen of N-MeBI preorganizes the conformation for accepting an H-bond from G-NH2. The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that N-MeBI-thiophene monomer compounds can strongly and selectively recognize single G•C bp sequences. Replacing the thiophene with other moieties significantly reduces binding affinity and specificity, as predicted by the design concept. These results show that the use of molecular features, such as sigma-hole, can lead to new approaches for small molecules in biomolecular interactions.

show abstract

“…To date, they have been successfully applied in cell culture experiments to modulate the activity of the hypoxia inducible factor 1α, the androgen receptor, and the glucocorticoid receptor by our laboratory (12)(13)(14)(15). Displacement of NF-kB by polyamides was also shown by electrophoretic mobility shift assays (16,17). Matsuda and co-workers independently demonstrated that a Py-Im polyamide could be used to target the TGF-β promoter (18).…”

mentioning

confidence: 99%

Modulation of NF-κB-dependent gene transcription using programmable DNA minor groove binders

Raskatov

Meier

Puckett

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

118

View full text Add to dashboard Cite

Nuclear factor κB (NF-κB) is a transcription factor that regulates various aspects of immune response, cell death, and differentiation as well as cancer. In this study we introduce the Py-Im polyamide 1 that binds preferentially to the sequences 5′-WGGWWW-3′ and 5′GGGWWW-3′. The compound is capable of binding to κB sites and reducing the expression of various NF-κB–driven genes including IL6 and IL8 by qRT-PCR. Chromatin immunoprecipitation experiments demonstrate a reduction of p65 occupancy within the proximal promoters of those genes. Genome-wide expression analysis by RNA-seq compares the DNA-binding polyamide with the well-characterized NF-κB inhibitor PS1145, identifies overlaps and differences in affected gene groups, and shows that both affect comparable numbers of TNF-α–inducible genes. Inhibition of NF-κB DNA binding via direct displacement of the transcription factor is a potential alternative to the existing antagonists.

show abstract

Programmable oligomers targeting 5′-GGGG-3′ in the minor groove of DNA and NF-κB binding inhibition

Cited by 21 publications

References 56 publications

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

A Novel High-Throughput Screening System Identifies a Small Molecule Repressive for Matrix Metalloproteinase-9 Expression

The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove

Modulation of NF-κB-dependent gene transcription using programmable DNA minor groove binders

Contact Info

Product

Resources

About