Journal article
NMR-driven discovery of benzoylanthranilic acid inhibitors of far upstream element binding protein binding to the human oncogene c-myc promoter
Journal of medicinal chemistry, Vol.47(20), pp.4851-4857
09/23/2004
DOI: 10.1021/jm0497803
PMID: 15369388
Abstract
Reversal of aberrant gene expression that is induced by the proto-oncogene c-myc is likely to be effective for treating a variety of tumors that rely on this pathway for growth. One strategy to down-regulate the c-myc pathway is to target transcription factors that regulate its own expression. A host of proteins act in coordination to regulate c-myc expression and any one of them are theoretical targets for small-molecule therapy. Experimentally, it has been shown that the far upstream element (FUSE) binding protein (FBP) is essential for c-myc expression, and reductions in FBP levels both reduce c-myc expression and correlate with slower cell growth. FBP binds to ssDNA by capturing exposed DNA bases in a hydrophobic pocket. This suggests that a small molecule could be designed to occupy this pocket and inhibit FBP function. Using a variety of screening methodologies, we have identified ligands that bind to the DNA binding pockets of the KH domains of FBP. Gel shift analyses using full length FBP and a related transcription factor confirm that a small-molecule lead compound inhibits DNA binding in a specific manner. The benzoylanthranilic acid compounds described here represent leads in the design of FBP inhibitors that can serve as useful tools in the study of c-myc regulation and in the development of therapeutics that target the c-myc pathway.
Details
- Title: Subtitle
- NMR-driven discovery of benzoylanthranilic acid inhibitors of far upstream element binding protein binding to the human oncogene c-myc promoter
- Creators
- Jeffrey R Huth - National Institute of Diabetes and Digestive and Kidney DiseasesLIPING YU - National Institute of Diabetes and Digestive and Kidney DiseasesG. Marius Clore - National Institute of Diabetes and Digestive and Kidney DiseasesDavid Levens - National Cancer InstitutePhilip J Hajduk - AbbottIrene Collins - National Institute of Diabetes and Digestive and Kidney DiseasesJamey Mack - AbbottRenaldo Mendoza - AbbottBinumol Isaac - National Institute of Diabetes and Digestive and Kidney DiseasesDemetrios T Braddock - National Institute of Diabetes and Digestive and Kidney DiseasesSteven W Muchmore - National Institute of Diabetes and Digestive and Kidney DiseasesKenneth M Comess - National Institute of Diabetes and Digestive and Kidney DiseasesStephen W Fesik - National Institute of Diabetes and Digestive and Kidney Diseases
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.47(20), pp.4851-4857
- Publisher
- American Chemical Society
- DOI
- 10.1021/jm0497803
- PMID
- 15369388
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Language
- English
- Date published
- 09/23/2004
- Academic Unit
- Biochemistry and Molecular Biology; Medicine Administration
- Record Identifier
- 9984627333602771
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