Abstract

Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented. The lead structure was rapidly optimised using a combination of crystal structures and effective docking models, with the best inhibitors exhibiting potent inhibitory activity on Haspin with IC₅₀ between 6 and 100 nM in vitro. The developed inhibitors displayed anti-proliferative properties against various human cancer cell lines in 2D and spheroid cultures and significantly inhibited the migration ability of osteosarcoma U-2 OS cells. Notably, we show that our lead compounds are powerful Haspin inhibitors in human cells, and did not block G2/M cell cycle transition due to improved selectivity against CDK1/CyclinB.

摘要

Haspin是通过调节Aurora B激酶的定位和活性以及组蛋白磷酸化来适当分裂细胞所需的一种有丝分裂蛋白激酶。在此建立了一系列基于CHR-6494和结构活性关系的咪唑并哒嗪。提出了对人的Haspin和其他几种蛋白激酶的前导结构的抑制活性的评估。结合晶体结构和有效的对接模型，对铅结构进行了快速优化，最佳的抑制剂在体外对Haspin表现出有效的抑制活性，IC ₅₀在6至100 nM之间。所开发的抑制剂在2D和球形培养物中显示出对各种人类癌细胞系的抗增殖特性，并显着抑制了骨肉瘤U-2 OS细胞的迁移能力。值得注意的是，我们证明了我们的先导化合物在人细胞中是强大的Haspin抑制剂，并且由于对CDK1 / CyclinB的选择性提高而没有阻止G2 / M细胞周期的转变。