吖啶类似物作为 HASPIN 和 DYRK2 激酶抑制剂的构效关系研究。
Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors.
机构信息
Brigham & Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA.
出版信息
Bioorg Med Chem Lett. 2010 Jun 15;20(12):3491-4.
Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50 <60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 <400 nM) with a 5.4-fold selectivity over haspin was also identified.
Haspin 是一种丝氨酸/苏氨酸激酶，对于完成正常有丝分裂是必需的，在细胞增殖过程中高度表达，包括在许多肿瘤中。因此，它已成为肿瘤学中一个有潜力的治疗靶点。对大约 140000 种化合物进行高通量筛选，发现吖啶类似物是一种有效的 Haspin 激酶抑制剂。对 270 种激酶的分析表明，该化合物对另一种丝氨酸/苏氨酸激酶 DYRK2 也表现出很强的抑制活性。对吖啶系列的优化研究表明，吖啶系列对 Haspin 和 DYRK2 的抑制的构效关系（SAR）有许多相似之处。然而，也注意到了一些结构上的差异，这使得生成一种有效的 Haspin 激酶抑制剂（33，IC50 <60 nM）成为可能，对 DYRK2 的选择性为 180 倍。此外，还鉴定出一种中度有效的 DYRK2 抑制剂（41，IC50 <400 nM），对 Haspin 的选择性为 5.4 倍。
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