Application of temperature sensitive yeast models with definite target in the screening of potential human Pin1 inhibitors.
- Author:
Jing ZHANG
;
Xiao-Min HAN
;
Wen-Hui HU
;
Zong-Ru GUO
;
Xiao-Bo HE
;
Shu-Yi SI
- Publication Type:Journal Article
- MeSH:
Animals;
Apoptosis;
drug effects;
Cell Proliferation;
drug effects;
Cyclin D1;
metabolism;
Drug Screening Assays, Antitumor;
methods;
G1 Phase;
High-Throughput Screening Assays;
methods;
Humans;
Mice;
NIMA-Interacting Peptidylprolyl Isomerase;
Neoplasms;
pathology;
Peptidylprolyl Isomerase;
antagonists & inhibitors;
Temperature;
Xenograft Model Antitumor Assays;
Yeasts
- From:
Acta Pharmaceutica Sinica
2014;49(6):854-860
- CountryChina
- Language:Chinese
-
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.
