AKT crystal structure and AKT-specific inhibitors
AKT crystal structure and AKT-specific inhibitors
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DOI：
10.1038/sj.onc.1209087
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发表时间：
2005-11-14
期刊：
影响因子：
8
通讯作者：
Madison, V
中科院分区：
文献类型：
--
作者：
Kumar, CC;Madison, V
AKT激酶是小分子药物发现的有吸引力的靶标，因为它们在肿瘤细胞存活/增殖中的关键作用以及它们在许多人类癌症中的过表达/活化。这篇综述总结了支持靶向AKT激酶的新药发现工作的基本原理的研究。AKT激酶在其非活性和活性状态下的结构特征，通过晶体结构分析确定，进行了描述。本文综述了近年来AKT小分子抑制剂的开发和生物学评价方面的研究进展，以及存在的问题。本文综述了以ATP结合位点、PH结构域和蛋白质底物结合位点为靶点的变构抑制剂以及异构体选择性变构抑制剂。基于结构的设计使用PKA突变体作为替代品和计算机建模的选择性抑制剂的发现进行了讨论。还讨论了不同类型的抑制剂作为治疗剂的发展所面临的问题和挑战。
AKT kinases are attractive targets for small molecule drug discovery because of their key role in tumor cell survival/proliferation and their overexpression/activation in many human cancers. This review summarizes studies that support the rationale for targeting AKT kinases in new drug discovery efforts. Structural features of AKT kinase in its inactive and active states, as determined by crystal structure analysis, are described. Recent efforts in the development and biological evaluation of small molecule inhibitors of AKT, and the challenges remaining are summarized. Inhibitors targeting the ATP binding site, PH domain and protein substrate binding site, as well as isoform selective allosteric inhibitors are reviewed. Structure-based design using PKA mutants as surrogates and computer modeling in the discovery of selective inhibitors is discussed. The issues and challenges facing the development of different classes of inhibitors as therapeutics are also discussed.