Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors.
Structure-activity relationship study of beta-carboline derivatives as haspin kinase inhibitors.
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DOI：
10.1016/j.bmcl.2012.01.028
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发表时间：
2012-03-01
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.;Ulyanova, Natalia P.;Patnaik, Debasis;Liu, Ji-Feng;Lin, Xiangjie;Auerbach, Ken;Ray, Soumya S.;Xian, Jun;Glicksman, Marcie A.;Stein, Ross L.;Higgins, Jonathan M. G.
Haspin 是一种丝氨酸/苏氨酸激酶，可磷酸化有丝分裂中组蛋白 H3 的 Thr-3，已成为可能的癌症治疗靶点。对大约 140,000 种化合物的高通量筛选确定了 β-咔啉 去氢骆驼蓬碱和哈啰酚为中等效力的 haspin 激酶抑制剂。根据先前对吖啶系列 haspin 抑制剂进行的结构-活性关系研究获得的信息，并使用最近公开的激酶晶体结构进行计算机对接，设计了去氢骆驼蓬碱类似物，从而显着增加了 haspin 激酶的抑制效力。与吖啶系列相比，去氢骆驼蓬碱衍生物对 DYRK2 的活性也较低。还介绍了去氢骆驼蓬碱系列代表性成员 (42, LDN-211898) 的体外小鼠肝微粒体稳定性和激酶谱。
Haspin is a serine/threonine kinase that phosphorylates Thr-3 of histone H3 in mitosis that has emerged as a possible cancer therapeutic target. High throughput screening of approximately 140,000 compounds identified the beta-carbolines harmine and harmol as moderately potent haspin kinase inhibitors. Based on information obtained from a structure-activity relationship study previously conducted for an acridine series of haspin inhibitors in conjunction with in silico docking using a recently disclosed crystal structure of the kinase, harmine analogs were designed that resulted in significantly increased haspin kinase inhibitory potency. The harmine derivatives also demonstrated less activity towards DYRK2 compared to the acridine series. In vitro mouse liver microsome stability and kinase profiling of a representative member of the harmine series (42, LDN-211898) are also presented.
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影响因子：
1.6
作者：
Higgins JM
通讯作者：
Higgins JM
DOI：
10.1126/science.1189435
发表时间：
2010-10-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Wang F;Dai J;Daum JR;Niedzialkowska E;Banerjee B;Stukenberg PT;Gorbsky GJ;Higgins JM
通讯作者：
Higgins JM
影响因子：
9.8
作者：
Kannan N;Taylor SS;Zhai Y;Venter JC;Manning G
通讯作者：
Manning G
影响因子：
8
作者：
Huertas, D.;Soler, M.;Moreto, J.;Villanueva, A.;Martinez, A.;Vidal, A.;Charlton, M.;Moffat, D.;Patel, S.;McDermott, J.;Owen, J.;Brotherton, D.;Krige, D.;Cuthill, S.;Esteller, M.
通讯作者：
Esteller, M.
影响因子：
4.8
作者：
Tanaka, H;Yoshimura, Y;Nishimune, Y
通讯作者：
Nishimune, Y