Inflammatory Cell Biology Laboratory, Department of Pharmacy and Pharmacology, University of Bath Bath, UK.
Front Immunol. 2012 Aug 2;3:226. doi: 10.3389/fimmu.2012.00226. eCollection 2012.
The predominant expression of the γ and δ isoforms of PI3K in cells of hematopoietic lineage prompted speculation that inhibitors of these isoforms could offer opportunities for selective targeting of PI3K in the immune system in a range of immune-related pathologies. While there has been some success in developing PI3Kδ inhibitors, progress in developing selective inhibitors of PI3Kγ has been rather disappointing. This has prompted the search for alternative targets with which to modulate PI3K signaling specifically in the immune system. One such target is the SH2 domain-containing inositol-5-phosphatase-1 (SHIP-1) which de-phosphorylates PI(3,4,5)P(3) at the D5 position of the inositol ring to create PI(3,4)P(2). In this article, we first describe the current state of PI3K isoform-selective inhibitor development. We then focus on the structure of SHIP-1 and its function in the immune system. Finally, we consider the current state of development of small molecule compounds that potently and selectively modulate SHIP activity and which offer novel opportunities to manipulate PI3K mediated signaling in the immune system.
PI3K 的γ和δ同工型在造血谱系细胞中的主要表达促使人们推测，这些同工型的抑制剂可能为在一系列与免疫相关的病理中选择性靶向免疫系统中的 PI3K 提供机会。虽然开发 PI3Kδ 抑制剂已经取得了一些成功，但开发选择性 PI3Kγ 抑制剂的进展却相当令人失望。这促使人们寻找其他替代靶点，以便特异性地在免疫系统中调节 PI3K 信号。其中一个靶点是含有 SH2 结构域的肌醇 5-磷酸酶-1（SHIP-1），它可以在肌醇环的 D5 位置将 PI(3,4,5)P(3)去磷酸化，生成 PI(3,4)P(2)。在本文中，我们首先描述了 PI3K 同工型选择性抑制剂的开发现状。然后，我们将重点介绍 SHIP-1 的结构及其在免疫系统中的功能。最后，我们考虑了目前开发强效和选择性调节 SHIP 活性的小分子化合物的现状，这些化合物为操纵免疫系统中 PI3K 介导的信号提供了新的机会。
