Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
Adv Exp Med Biol. 2020;1274:203-222. doi: 10.1007/978-3-030-50621-6_9.
The lipid kinases that generate the lipid signalling phosphoinositides have been established as fundamental signalling enzymes that control numerous aspects of how cells respond to their extracellular environment. In addition, they play critical roles in regulating membrane trafficking and lipid transport within the cell. The class I phosphoinositide kinases which generate the critical lipid signal PIP are hyperactivated in numerous human pathologies including cancer, overgrowth syndromes, and primary immunodeficiencies. The type III phosphatidylinositol 4-kinase beta isoform (PI4KB), which are evolutionarily similar to the class I PI3Ks, have been found to be essential host factors mediating the replication of numerous devastating pathogenic viruses. Finally, targeting the parasite variant of PI4KB has been established as one of the most promising strategies for the development of anti-malarial and anti-cryptosporidium strategies. Therefore, the development of targeted isoform selective inhibitors for these enzymes are of paramount importance. The first generation of PI3K inhibitors have recently been clinically approved for a number of different cancers, highlighting their therapeutic value. This review will examine the history of the class I PI3Ks, and the type III PI4Ks, their relevance to human disease, and the structural basis for their regulation and inhibition by potent and selective inhibitors.
生成脂质信号磷脂酰肌醇的脂质激酶已被确立为基本的信号酶，它们控制着细胞对外界环境反应的许多方面。此外，它们在调节细胞内的膜运输和脂质运输方面也起着关键作用。在包括癌症、过度生长综合征和原发性免疫缺陷在内的许多人类疾病中，生成关键脂质信号 PIP 的 I 类磷酸肌醇激酶被过度激活。III 型磷脂酰肌醇 4-激酶β同工型（PI4KB）与 I 类 PI3Ks 在进化上相似，已被发现是介导多种致命致病性病毒复制的必需宿主因子。最后，针对 PI4KB 的寄生虫变体已被确定为开发抗疟原虫和抗隐孢子虫策略的最有前途的策略之一。因此，开发针对这些酶的靶向同工型选择性抑制剂至关重要。第一代 PI3K 抑制剂最近已在临床上批准用于多种不同的癌症，突出了它们的治疗价值。这篇综述将探讨 I 类 PI3Ks 和 III 型 PI4Ks 的历史，它们与人类疾病的相关性，以及它们的调节和被有效和选择性抑制剂抑制的结构基础。
