Laboratory for Drug Discovery in Neurodegeneration, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Bioorg Med Chem Lett. 2012 Mar 1;22(5):2015-9. doi: 10.1016/j.bmcl.2012.01.028. Epub 2012 Jan 28.
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.
Haspin 是一种丝氨酸/苏氨酸激酶，可在有丝分裂中磷酸化组蛋白 H3 的 Thr-3，已成为可能的癌症治疗靶点。对大约 140,000 种化合物进行高通量筛选，发现β-咔啉类化合物哈尔明和哈尔醇是中度有效的 Haspin 激酶抑制剂。基于之前对吖啶系列 Haspin 抑制剂进行的构效关系研究以及最近公开的激酶晶体结构的计算机对接信息，设计了哈尔明类似物，使 Haspin 激酶抑制活性显著提高。与吖啶系列相比，哈尔明衍生物对 DYRK2 的活性也较低。本文还介绍了哈尔明系列的一个代表性成员（42，LDN-211898）的体外小鼠肝微粒体稳定性和激酶谱。
