Haspin抑制剂的合成与生物学评价：激酶抑制活性和细胞活性
Synthesis and biological evaluation of Haspin inhibitors: Kinase inhibitory potency and cellular activity.
作者信息
Zeinyeh Wael, Esvan Yannick J, Josselin Béatrice, Defois Mathilde, Baratte Blandine, Knapp Stefan, Chaikuad Apirat, Anizon Fabrice, Giraud Francis, Ruchaud Sandrine, Moreau Pascale
机构信息
Université Clermont Auvergne, CNRS, Clermont Auvergne INP, ICCF, F-63000, Clermont-Ferrand, France.
Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680, Roscoff, France; Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening Facility), Station Biologique de Roscoff, 29680, Roscoff, France.
出版信息
Eur J Med Chem. 2022 Jun 5;236:114369. doi: 10.1016/j.ejmech.2022.114369. Epub 2022 Apr 9.
Haspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography.
Haspin（单倍体生殖细胞特异性核蛋白激酶）为新型抗癌药物的研发提供了一个潜在靶点。因此，鉴定靶向这种蛋白激酶的新型抑制剂备受关注。然而，迄今为止开发的Haspin抑制剂对人类激酶组中的其他蛋白激酶表现出较差的选择性。在此，我们鉴定出一种新型的基于吡啶并喹唑啉的抑制剂（4），对Haspin具有优异的抑制活性和选择性（IC50为50 nM）。我们描述了结构-活性关系研究，包括在486种激酶以及永生化或癌细胞系的大样本中对该抑制剂的评估。此外，我们利用X射线晶体学确定了类似物2a与Haspin复合物的结合模式。
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