title: Gaining insights into the small molecule targeting of the G-quadruplex in the c-MYC promoter using NMR and an allele-specific transcriptional assay.
abstract: G-quadruplexes (four-stranded DNA secondary structures) are showing promise as new targets for anticancer therapies. Specifically, G-quadruplexes in the proximal promoter region of regulatory genes have the potential to act as silencer elements and thereby turn off transcription. Thus, compounds that are capable of binding to and stabilizing G-quadruplexes would be of great benefit. In this chapter we describe two recent studies from our labs. In the first case, we use NMR to elucidate the structure of a 2:1 complex between a small molecule and the G-quadruplex in the c-MYC promoter. In the second case, we use an allele-specific transcription assay to demonstrate that the effect of a G-quadruplex-interactive compound is mediated directly through the G-quadruplex. Finally, we use this information to propose models for the interaction of various small molecules with the c-MYC G-quadruplex.
authors: College of Pharmacy, University of Arizona, 1703 E. Mabel Street, Tucson, AZ, 85721, USA.
authors: Christine E
authors: CE
authors: Kaiser
authors: Vijay
authors: V
authors: Gokhale
authors: Danzhou
authors: D
authors: Yang
authors: Laurence H
authors: LH
authors: Hurley
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001483:Base Sequence; D054856:G-Quadruplexes / Q000187:drug effects*; D016259:Genes, myc / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D011804:Quinolines; D054852:Small Molecule Libraries; C016712:quindoline