Design,synthesis And Activity Determination Of Novel Macrocyclic PIM-1 Kinase Inhibitors

Pim-1 kinase can regulate a variety of biological processes of the cell cycle and is involved in many important signaling pathways related to cancer cells.It plays an important role in the formation and development about tumors.Therefore,the research of novel and effective Pim-1 kinase inhibitors is of great significance for the treatment of tumors.In this paper,the macrocyclization of 10-DEBC was carried out by virtual screening,and a modification strategy for the macrocyclization of the compound 10-DEBC was proposed:The spatial conformation of macrocyclic derivatives was optimized and evaluated by molecular dynamics simulation,and the macrocyclic derivative which has the strongest affinity with Pim-1kinase was screened out.Four synthetic routes of benzo[b]pyridine[4,3-e][1,4]oxazine compounds were designed and explored.Ten macrocyclic compounds with 14 to 16-membered ring were synthesized and their structures were confirmed.Their biological activities were determined by ADP-Glo kinase assay.The results showed that the inhibitory activity of H1(IC₅₀=433.7 n M)was significantly improved compared with the lead compound 10-DEBC(IC₅₀=2340 n M).Three compounds with high inhibitory activity were obtained by further structural modification of H1.The inhibitory activity of H3,H5 and H10 were IC₅₀=81.49 n M,35.13 n M and 57.34 n M which were about 5,12 and 8 times higher than that of H1 respectively.Based on the test results of Pim-1 kinase inhibitory activity and the protein crystal structure of compound H3 and Pim-1 kinase,the preliminary structure-activity relationship is summarized:（1）The nitrogen atom of the aliphatic chain of macrocyclic compound forms a good salt bridge interaction with Asp128;（2）The pyridine nitrogen atom of the benzo[b]pyridine[4,3-e][1,4]oxazine ring region forms a hydrogen bond with Lys67 in the kinase hinge region;（3）The macrocyclic structure provides a continuous hydrophobic surface extending to the hydrophobic pocket space of Pim-1kinase,which may enhance the hydrophobic interaction between the macrocyclic side chain and hydrophobic amino acids,and stabilize the conformation of the compound,which is beneficial to improve the activity.