Drug targeting of secondary DNA structures in oncogene promoter elements

CARB 29

Laurence H. Hurley, hurley@pharmacy.arizona.edu, College of Pharmacy, The University of Arizona, 1703 E Mabel, BIO5 Collaborative Research Institute, Tucson, AZ 85721
Recent evidence points toward the importance of secondary DNA structures, including G-quadruplex and i-motifs, in promoter regions of oncogenes, including c-Myc, Bcl-2, VEGF, Hif-1Ą, c-kit, PDGF-A, kRas, RB, and RET. These elements are found within regions that are nuclease hypersensitivity elements and are in proximity to transcriptional start sites. Examination of the sequences show conserved sequence motifs that in many cases can be used to predict the folding patterns of these secondary DNA structures. The biological role of these secondary DNA structures in transcriptional regulation can vary such that in some cases they are the repressor elements, while in others they activate transcription. Last, strategies that have led to the development of a first-in-class drug that targets G-quadruplexes will be described.