Molecular recognition of DNA by small molecules: Fundamentals to applications

Abstract

Many human diseases are caused by dysregulated gene expression. The oversupply or overactivity of one or more transcription factors may be required for the survival, growth, and metastatic behavior of human cancers. Pyrrole-imidazole polyamides are small mols. programmed to read the DNA double helix by a set of simple chem. principles. These oligomers achieve affinities and specificities comparable to DNA-binding proteins. Research efforts are focused on the modulation of gene expression pathways by disruption of protein-DNA interfaces. Py-Im polyamides interfere with RNA polymerase II activity in cell culture and result in dose-dependent depletion of the RNA polymerase II large subunit. A hairpin Py-Im polyamide targeted to the androgen receptor half-site was found to exert antitumor effects against prostate cancer xenografts. We have identified hairpin oligomers that cause no significant evidence of mouse toxicity at doses less than 10mg/kg and retain activity against LNCaP xenografts.