Towards Gram-positive antivirulence drugs: new inhibitors of Streptococcus agalactiae Stk1.
Towards Gram-positive antivirulence drugs: new inhibitors of Streptococcus agalactiae Stk1.
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DOI：
10.1016/j.bmcl.2010.04.150
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发表时间：
2010-06-15
影响因子：
2.7
通讯作者：
Higgins, Jonathan M. G.
中科院分区：
文献类型：
--
作者：
Cuny, Gregory D.;Robin, Maxime;Ulyanova, Natalia P.;Patnaik, Debasis;Pique, Valerie;Casano, Gilles;Liu, Ji-Feng;Lin, Xiangjie;Xian, Jun;Glicksman, Marcie A.;Stein, Ross L.;Higgins, Jonathan M. G.
Haspin是完成正常有丝分裂所需的丝氨酸/苏氨酸激酶，其在细胞增殖期间高度表达，包括在许多肿瘤中。因此，它已成为肿瘤学中潜在的治疗靶点。约140，000种化合物的高通量筛选鉴定了吖啶类似物作为有效的haspin激酶抑制剂。对一组270种激酶的分析显示，该化合物还对另一种丝氨酸/苏氨酸激酶DYRK 2表现出有效的抑制活性。吖啶系列的优化研究表明，吖啶系列对haspin和DYRK 2抑制的构效关系（SAR）有许多相似之处。然而，注意到几个结构差异允许产生有效的haspin激酶抑制剂（33，IC 50 < 60 nM），其选择性是DYRK 2的180倍。此外，还鉴定了一种中等效力的DYRK 2抑制剂（41，IC 50 < 400 nM），其选择性是haspin的5.4倍。
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.
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影响因子：
1.6
作者：
Higgins JM
通讯作者：
Higgins JM
影响因子：
158.5
作者：
Dave, Sandeep S.;Fu, Kai;Staudt, Louis M.
通讯作者：
Staudt, Louis M.
影响因子：
4.8
作者：
Tanaka, H;Yoshimura, Y;Nishimune, Y
通讯作者：
Nishimune, Y
影响因子：
3.5
作者：
Polioudaki, H;Markaki, Y;Georgatos, SD
通讯作者：
Georgatos, SD
影响因子：
11.8
作者：
Dai, Jun;Sullivan, Beth A.;Higgins, Jonathan M. G.
通讯作者：
Higgins, Jonathan M. G.