title: [Application of temperature sensitive yeast models with definite target in the screening of potential human Pin1 inhibitors].
abstract: This study is to explore new lead compounds by inhibition of Pin1 for anticancer therapy using temperature sensitive mutants. As Pin1 is conserved from yeast to human, we established a high-throughput screening method for Pin1 inhibitors, which employed yeast assay. This method led to the identification of one potent hits, 8-11. In vitro, 8-11 inhibited purified Pin1 enzyme activity with IC50 of (10.40 +/- 1.68) micromol x L(-1), induced G1 phase arrest and apoptosis, showed inhibitory effects on a series of cancer cell proliferation, reduced Cyclin D1 expression, was defined as reciprocally matched for protein-ligand complex in virtual docking analysis and reduced cell migration ability. In vivo, we could observe reduction of tumor volume after treatment with 8-11 in xenograft mice compared with vehicle DMSO treatment. Altogether, these results provide for the first time the involvement of 8-11 in the anticancer activity against Pin1.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiao-Min
authors.initials: XM
authors.lastname: Han
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Hu
authors.forename: Zong-Ru
authors.initials: ZR
authors.lastname: Guo
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: He
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Si
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D016193:G1 Phase; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009369:Neoplasms / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors*; D013696:Temperature; D023041:Xenograft Model Antitumor Assays; D015003:Yeasts
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019938:Cyclin D1; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse