title: The design of novel 17beta-hydroxysteroid dehydrogenase type 3 inhibitors.
abstract: 17beta-Hydroxysteroid dehydrogenase type 3 (17beta-HSD3) is expressed at high levels in the testes and seminal vesicles but has also been shown to be present in prostate tissue, suggesting its potential involvement in both gonadal and non-gonadal testosterone biosynthesis. The role of 17beta-HSD3 in testosterone biosynthesis makes this enzyme an attractive molecular target for small molecule inhibitors for the treatment of prostate cancer. Here we report the design of selective inhibitors of 17beta-HSD3 as potential anti-cancer agents. Due to 17beta-HSD3 being a membrane-bound protein a crystal structure is not yet available. A homology model of 17beta-HSD3 has been built to aid structure-based drug design. This model has been used with docking studies to identify a series of lead compounds that may give an insight as to how inhibitors interact with the active site. Compound 1 was identified as a potent selective inhibitor of 17beta-HSD3 with an IC(50)=700nM resulting in the discovery of a novel lead series for further optimisation. Using our homology model as a tool for inhibitor design compound 5 was discovered as a novel potent and selective inhibitor of 17beta-HSD3 with an IC(50) approximately 200nM.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Bath BA2 7AY, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Sharland
authors.forename: Wesley B
authors.initials: WB
authors.lastname: Heaton
authors.forename: Ana M Ramos
authors.initials: AM
authors.lastname: Gonzalez
authors.forename: Helen V
authors.initials: HV
authors.lastname: Bailey
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Springall
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Day
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Tutill
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000145:classification; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D040681:Structural Homology, Protein
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; D010880:Piperidines; C032727:piperidine; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3