Pim-1 kinase is a serine/threonine kinase which is vital in many tumors. The Pim-1 inhibitor 10-DEBC and its derivatives discovered in our previous work were modified through macrocyclization strategy. A series of benzo[b]pyridine[4,3-e][1,4]oxazine macrocyclic compounds were designed, synthesized, and evaluated as novel Pim-1 kinase inhibitors. Among these compounds, compound H5 exhibited the highest activity with an IC₅₀ value of 35 nM. In addition, the crystal complex structure of Pim-1 kinase bound with compound H3 was determined, and the structure–activity relationship of these macrocyclic compounds was analyzed, which provides the structural basis of further optimization of novel macrocyclic Pim-1 kinase inhibitors..

Pim-1 激酶是一种丝氨酸/苏氨酸激酶，在许多肿瘤中都至关重要。在我们之前的工作中发现的 Pim-1 抑制剂10-DEBC及其衍生物通过大环化策略进行了修饰。一系列苯并[ b ]吡啶[4,3-e][1,4]恶嗪大环化合物被设计、合成并评估为新型Pim-1激酶抑制剂。在这些化合物中，化合物H5表现出最高的活性，IC ₅₀值为35 nM。此外，与化合物H3结合的 Pim-1 激酶的晶体复杂结构确定了这些大环化合物的构效关系，为进一步优化新型大环Pim-1激酶抑制剂提供了结构基础。