NMR-driven discovery of benzoylanthranilic acid inhibitors of far upstream element binding protein binding to the human oncogene c-myc promoter.
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.
Huth
Jeffrey R
JR
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA.
Yu
Liping
L
Collins
Irene
I
Mack
Jamey
J
Mendoza
Renaldo
R
Isaac
Binumol
B
Braddock
Demetrios T
DT
Muchmore
Steven W
SW
Comess
Kenneth M
KM
Fesik
Stephen W
SW
Clore
G Marius
GM
Levens
David
D
Hajduk
Philip J
PJ
D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004265:DNA Helicases; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D016259:Genes, myc; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins; D020449:Repetitive Sequences, Amino Acid; D013329:Structure-Activity Relationship
D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D008024:Ligands; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016601:RNA-Binding Proteins; D004265:DNA Helicases