Molecular Design And Synthesis Of RSK Inhibitors And Preliminary Evaluation Of Their Anti-breast Cancer Activity

RSK is called P90 ribosomal S6 kinase（P90 ribosomal S6 kinase）.It belongs to one of the four serine/threonine kinase families.It can regulate a variety of cellular processes,such as proliferation,survival,movement,transcription,etc.And can phosphorylate a variety of proteins.Phosphorylation refers to the process in which the hydroxyl groups on protein amino acids are replaced by phosphate groups.Therefore,RSK also plays an important role in protein conversion.RSK is also one of the new targets for the development of anti-cancer drugs,and its indications include breast cancer,pancreatic cancer,lung cancer and so on.However,most RSK kinase inhibitors have not yet reached clinical effects and have many side effects.In this thesis,the known RSK inhibitor LJH685 is used as the leading compound,through molecular docking to simulate the binding position of the molecule in the protein,a total of 57 compounds were synthesized.The main strategy is to replace the two benzene rings connected by the Al aryl ring.The structures of all compounds were confirmed by ~1H-NMR and ¹³C-NMR,and some compounds were confirmed by MS.Among them,two new compounds showed obvious RSK inhibition ability.Using HCC1806 cells as experimental cells,all compounds were tested for their anti-RSK activity and anti-tumor activity.The results show that the ability of RSK-20/29/38to inhibit the phosphorylation of YB1 is almost the same level as that of LJH685.Among them,in terms of inhibiting cell proliferation,cell cycle and cell cycle-related proteins,compound RSK-38（10c）compound which has a significant inhibitory effect on HCC1806 cell proliferation and cell cycle,and is better than its leading compound LJH685.In terms of cyclins,RSK-38 compounds can down-regulate the expression of cyclin D1,inhibit the expression of p-YB1 and KLF5,and up-regulate the expression of p21 and p27,which are better than those of compound LJH685.In summary,compared with LJH685 and RSK-20/29,compound RSK-38（10c）can significantly block the cell cycle and inhibit cell proliferation.