title: Binary and ternary crystal structure analyses of a novel inhibitor with 17beta-HSD type 1: a lead compound for breast cancer therapy.
abstract: Oestradiol is a well-characterized sex hormone that stimulates breast cancer and other oestrogen-related diseases. 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses the last step in the synthesis of oestradiol and androstenediol in breast tumour tissue. The enzyme's high expression and activity after simultaneous blockade of oestrogen receptors and inhibition of aromatase in the tumour shows the necessity for its inhibition as a requirement for breast cancer therapy. In the present paper, we report structures of the binary and ternary complexes of 17beta-HSD1 with a new inhibitor E2B {3-[3',17'beta-dihydroxyestra-1',3',5'(10')-trien-16'beta-methyl]benzamide}, and the enzyme inhibition by the later. The IC50 value for E2B was determined to be 42 nM in T47D cells. Multiple interactions between E2B and the enzyme include hydrogen bonds and hydrophobic interactions, as well as pi-pi interactions. A kinetic study demonstrated that E2B inhibits the enzyme's reduction forming oestradiol from oestrone, with a Ki of 0.9+/-0.15 nM. Such strong inhibition is in agreement with its extensive interaction with the enzyme, suggesting its potential as a lead compound for breast cancer therapy. In fact, this possibility is enhanced by its capacity for cell penetration similar to natural steroids. Such inhibitors that block oestrogen synthesis to suppress the sulfatase pathway producing oestradiol can be used in adjuvant therapies with oestrogen receptor blockade, opening a new orientation of breast cancer treatment.
authors.affiliation: Laboratory of Molecular Endocrinology and Oncology, CHUL Research Center (Centre Hospitalier de Université Laval, CHUQ) and Laval University, Quebec, Canada, G1V 4G2.
authors.forename: Mausumi
authors.initials: M
authors.lastname: Mazumdar
authors.forename: Diane
authors.initials: D
authors.lastname: Fournier
authors.forename: Dao-Wei
authors.initials: DW
authors.lastname: Zhu
authors.forename: Christine
authors.initials: C
authors.lastname: Cadot
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
authors.forename: Sheng-Xiang
authors.initials: SX
authors.lastname: Lin
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004970:Estrone / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: C546335:3-(3',17'-dihydroxyestra-1',3',5'(10')-trien-16'-methyl)benzamide; D001549:Benzamides; D004791:Enzyme Inhibitors; D004970:Estrone; D004958:Estradiol; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase