title: Novel aromatase inhibitors by structure-guided design.
abstract: Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.
authors.affiliation: Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA. ghoshd@upstate.edu
authors.forename: Debashis
authors.initials: D
authors.lastname: Ghosh
authors.forename: Jessica
authors.initials: J
authors.lastname: Lo
authors.forename: Daniel
authors.initials: D
authors.lastname: Morton
authors.forename: Damien
authors.initials: D
authors.lastname: Valette
authors.forename: Jingle
authors.initials: J
authors.lastname: Xi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Griswold
authors.forename: Susan
authors.initials: S
authors.lastname: Hubbell
authors.forename: Chinaza
authors.initials: C
authors.lastname: Egbuta
authors.forename: Wenhua
authors.initials: W
authors.lastname: Jiang
authors.forename: Jing
authors.initials: J
authors.lastname: An
authors.forename: Huw M L
authors.initials: HM
authors.lastname: Davies
mesh_terms: D000730:Androstadienes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors