Structural basis of inhibitor specificity of the human protooncogene proviral insertion site in Moloney murine leukemia virus (PIM-1) kinase
Structural basis of inhibitor specificity of the human protooncogene proviral insertion site in Moloney murine leukemia virus (PIM-1) kinase
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DOI：
10.1021/jm0504858
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发表时间：
2005-12-01
影响因子：
7.3
通讯作者：
Knapp, S
中科院分区：
文献类型：
--
作者：
Bullock, AN;Debreczeni, JÉ;Knapp, S
激酶PIM-1在细胞因子信号传导中起关键作用，并与许多肿瘤的发展有关。PIM-1的三维结构的特征在于独特的铰链区，其缺乏第二氢键供体，并且使得确定抑制剂如何结合该激酶特别重要。我们确定了PIM-1与双吲哚马来酰亚胺（BIM-1）复合物的结构，并建立了该类抑制剂的构效关系（SAR）。此外，我们筛选了激酶靶向文库并鉴定了许多PIM-1的高亲和力抑制剂，如咪唑并[1，2-B]哒嗪、吡唑并[1，5 a]嘧啶和类黄酮家族的成员。在本文中，我们提出了一个初步的SAR的基础上确定的热稳定性变化测定，量热结合数据，和生化分析，可能会发现应用程序的PIM-1依赖性癌症类型的治疗所确定的支架。
The kinase PIM-1 plays a pivotal role in cytokine signaling and is implicated in the development of a number of tumors. The three-dimensional structure of PIM-1 is characterized by an unique hinge region which lacks a second hydrogen bond donor and makes it particularly important to determine how inhibitors bind to this kinase. We determined the structures of PIM-1 in complex with bisindolylmaleimide (BIM-1) and established the structure-activity relationship (SAR) for this inhibitor class. In addition, we screened a kinase targeted library and identified a number of high affinity inhibitors of PIM-1 such as imidazo[1,2-b]pyridazines, pyrazolo[1,5a]pyrimidines, and members of the flavonoid family. In this paper we present an initial SAR of the identified scaffolds determined on the basis of a thermostability shift assay, calorimetric binding data, and biochemical assays which may find applications for the treatment of PIM-1 dependent cancer types.