An ARE-selective DNA minor groove binder from a combinatorial approach.
A synthetic combinatorial library of 10,000 components mostly containing aromatic amino acids was screened for inhibition of DNase I cleavage at two ARE sequences. Ten amino acid building blocks were used to generate the library in which the N and C terminal residues were fixed and the four central positions of the peptide ligands were varied. The DNase I footprinting assay led, after deconvolution through sublibrary synthesis, to the identification of CGL-6382 as an ARE-selective minor groove binder containing a N-terminal nicotinic acid motif adjacent to a N-methylimidazole unit and three N-methylpyrrole units coupled to a C-terminal argininamide residue. The optimized ligand CGL-6382 was found to recognize a 5'-GC(A/T)(A/T) motif within the two cloned androgen receptors responsive elements. The discovery of CGL-6382 as an ARE-selective ligand augurs well for the use of the DNase I footprinting methodology to identify sequence-specific DNA recognition ligands from large mixtures of small molecules.
Hamy
F
F
Department of Oncology, Novartis Pharma Research, Basel, CH-4002, Switzerland. francois.hamy@pharma.novartis.com
Albrecht
G
G
Flörsheimer
A
A
Bailly
C
C
D001483:Base Sequence; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018983:DNA Footprinting; D003850:Deoxyribonuclease I / Q000378:metabolism
D004247:DNA; D003850:Deoxyribonuclease I