title: Discovery of novel fatty acid synthase (FAS) inhibitors based on the structure of ketoaceyl synthase (KS) domain.
abstract: Development of fatty acid synthase (FAS) inhibitors has increasingly attracted much attention in recent years due to their potential therapeutic use in obesity and cancers. In this investigation, pharmacophore modeling based on the first crystal structure of human KS domain of FAS was carried out. The established pharmacophore model was taken as a 3D query for retrieving potent FAS inhibitors from the chemical database Specs. Docking study was further carried out to refine the obtained hit compounds. Finally, a total of 28 compounds were selected based on the ranking order and visual examination, which were first evaluated by a cell line-based assay. Seven compounds that have good inhibition activity against two FAS overexpressing cancer cell lines were further evaluated by an enzyme-based assay. One compound with a new chemical scaffold was found to have low micromolar inhibition potency against FAS, which has been subjected to further chemical structural modification.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Sichuan 610041, China.
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Zeng
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.forename: Hui-Jin
authors.initials: HJ
authors.lastname: Fan
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wang
authors.forename: Pan
authors.initials: P
authors.lastname: Ji
authors.forename: Ze-Rong
authors.initials: ZR
authors.lastname: Wang
authors.forename: Shuang
authors.initials: S
authors.lastname: Ma
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Li
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Ma
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D064429:Fatty Acid Synthases