The Design,Synthesis And Bioactivity Evaluation Of Small-molecule Inhibitors Of PD-1

In recent years,there's increasing study and focus on immunotherapy for cancer,which stimulate body's immune system to fight against cancer.Cancer immunotherapy has become one of the most promising method in the field of cancer therapy.Immune checkpoint inhibitors are the most clinically mature in the develop-ment of immunotherapy,especially targeting PD-1/PDL1 and CTLA-4.Until now,antibodies targeting the PD-1/PD-L1 immune checkpoint achieved spectacular success in anticancer therapy.Five monoclonal antibodies including Keytruda,Opdivo,Tecentriq,Bavencio,and Imfinzi based on the PD-1/PD-L1 pathway has been successfully applied in clinical treatment of cancer.In clinic,small molecule inhibitors have some advantages over antibody,such as few immunogenicity side effects,better druggability and less cost.Therefore,the development of safer and more effective small-molecule inhibitors remains an attractive approach for cancer treatment.While few small molecule inhibitors have been reported so far.The thesis research is the Design,synthesis and bioactivity evaluation of small molecule inhibitors of PD-1.The main purpose of this thesis is to design and synthesis of small molecule inhibitors targeting PD-1 Checkpoint Pathway using fragment based drug design technology.Structure-based virtual screening of chembridge fragments library was performed to seek small molecules of potential activation of the PD-1.After that,100 molecules were screened out.Then,binding bode analysis was performed to confirm the molecular skeletons which have binding activity.50 compounds were designed based on the principle of spatial matching and energy matching using fragment growth strategy.In the end,retrosynthetic analysis was performed to find possible synthetic method.So far,40 compounds were synthesized and characterized using nuclear magnetic resonance,x-ray crystalline diffraction,etc.6 of them have crystal structure.In addition,the ELISA test was performed to evaluate the bioactivity of the compounds.Further more,molecular docking and molecular dynamics simulation were performed to explore the interaction mode between small molecule and protein.In conclusion,10 compounds which have inhibitory activity targeting PD-1/PD-L1 Immune checkpoint pathway were designed and synthesized.This work establishes the foundation for the drug discovery which targeting PD-1/PD-L1 Immune checkpoint pathway.