title: Structural analysis and biological activities of BXL0124, a gemini analog of vitamin D.
abstract: Gemini analogs of calcitriol, characterized by the extension of the C21-methyl group of calcitriol with a second chain, act as agonists of the vitamin D receptor (VDR). This second side chain of gemini is accommodated in a new cavity inside the VDR created by the structural rearrangement of the protein core. The resulting conformational change preserves the active state of the receptor and bestows gemini compounds with biological activities that exceed those of calcitriol. Of particular interest are gemini's anti-cancer properties, and in this study we demonstrate anti-proliferative and tumor-reducing abilities of BXL0124 and BXL0097, differing only by the presence or absence, respectively, of the methylene group on the A ring. BXL0124 acts as a more potent VDR agonist than its 19-nor counterpart by activating VDR-mediated transcription at lower concentrations. In a similar manner, BXL0124 is more active than BXL0097 in growth inhibition of breast cancer cells and reduction of tumor volume. Structural comparisons of BXL0097 and BXL0124, as their VDR complexes, explain the elevated activity of the latter.
authors.affiliation: Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, Illkirch, France; Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France; Université de Strasbourg, Strasbourg, France.
authors.forename: Anna Y
authors.initials: AY
authors.lastname: Belorusova
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Hong Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: So
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Hubert
authors.initials: H
authors.lastname: Maehr
authors.affiliation: Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, Illkirch, France; Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Illkirch, France; Université de Strasbourg, Strasbourg, France. Electronic address: rochel@igbmc.fr.
authors.forename: Natacha
authors.initials: N
authors.lastname: Rochel
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D016513:Mice, SCID; D062105:Molecular Docking Simulation; D018167:Receptors, Calcitriol / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014815:Vitamins / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C552206:1,25-dihydroxy-21-(3-hydroxy-3-methyl-4,4,4-tributyl)-23-yne-26,27-hexafluorocholecalciferol; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014815:Vitamins; D002117:Calcitriol
keywords: Breast cancer; Gemini analog; VDR agonist; Vitamin D; Vitamin D analog