Study On The Novel KLK7 Inhibitors:Screening And Research In Pancreatic Cancer Cell PANC-1

Objective: The expression of kallikrein-related peptidase 7(KLK7)is increased in human pancreatic cancer.It is closely related to the poor prognosis of pancreatic cancer.A large number of studies have shown that KLK7 plays an important role in the development of pancreatic cancer,which could be a potential target for the treatment of pancreatic cancer.The aim of this study is based on KLK7 to screen novel inhibitors and test the effect of the inhibitor on the proliferation,migration and invasion of PANC-1 cell,and provide a theoretical basis for the development of KLK7 as a therapeutic target for pancreatic cancer.Methods:(1)Using computer assisted drug screening technology,we searched the structure of pharmacophore model based on KLK7 in a large capacity database to obtain the conformation of the KLK7 targeting inhibitors.(2)Compounds were synthesized according to the selected molecular structure,to evaluate the effect of the inhibitor on the activity of KLK7.The rate of the fluorescence substrate(Mca-R-P-K-P-V-E-Nval-W-R-K(Dnp)-NH2)catalyzed(exc=320nm,em=405nm)by KLK7 was measured.(3)Pancreatic cancer cell line(PANC-1)and human hepatoma cell line(HepG-2)were taken as the research objects.RTCA technology was used to detect the inhibitory effect of KLK7 inhibitor on the proliferation,migration and invasion of tumor cells and the compound(Compound 8)was selected for different concentration gradient.(4)Selected a inhibitory inhibitor(Compound 42)to conduct a controlled study on PANC-1 and HepG-2 cells,and the inhibitory effects were observed.Results:(1)The molecular conformation of a novel KLK7 inhibitor was obtained by using KLK7 as a target for virtual screening by the technology of computer aided drug screening,and a small molecule compound(Compound 8)was synthesized.(2)The RTCA results demonstrated that the inhibitory effect of the inhibitor on the proliferation,migration and invasion of pancreatic cancer cell line PANC-1 cells gradually increased with the increase of the concentration of the inhibitor in a certain concentration range,but had no inhibitory effect on HepG-2 cells.(3)KLK7 control inhibitor(Compound 42)has same effect on the proliferation,migration and invasion of PANC-1 cells.Conclusion: This study successfully screened a novel target inhibitor of KLK7.In vitro experiments showed that the inhibitor could inhibit the proliferation,migration and invasion of pancreatic cancer PANC-1 cell.It provides a theoretical basis for further research in vivo.It is a new potential targeted drug for the treatment of pancreatic cancer.