Small-molecule agonists of SHEP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells
Small-molecule agonists of SHEP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells
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DOI：
10.1182/blood-2007-03-079699
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发表时间：
2007-09-15
期刊：
影响因子：
20.3
通讯作者：
Mui, Alice L. -F.
中科院分区：
文献类型：
--
作者：
Ong, Christopher J.;Ming-Lum, Andrew;Mui, Alice L. -F.
由于磷酸肌肽3-激酶（PI3K）在细胞活化、增殖和存活中起着核心作用，因此针对PI3K通路成分的药物抑制剂正被积极开发用于治疗炎症性疾病和癌症。这些靶向药物抑制PI3K本身或下游蛋白激酶的活性。然而，一种以前未开发的替代策略是激活该途径中的负调控磷酸酶。含有sh2的肌醇-5'-磷酸酶SHIP1是免疫/造血细胞中PI3K的正常生理反调节因子，它水解PI3K的产物磷脂酰肌醇-3,4,5-三磷酸（PIPS）。我们现在描述了SHIP1强效和特异性小分子激活剂的鉴定和表征。这些化合物代表了磷酸酶的第一个小分子激活剂，能够在体外激活重组SHIP1酶并刺激SHIP1细胞。这些化合物的活化机制研究表明，它们结合了SHIP1中先前未描述的变构活化结构域。此外，体内给药这些化合物对内毒素血症和急性皮肤过敏反应的小鼠模型具有保护作用，这表明SHIP1激动剂可以用于治疗抑制PI3K途径。完整巨噬细胞和肥大细胞的活性
Because phosphoinositide 3-kinase (PI3K) plays a central role in cellular activation, proliferation, and survival, pharmacologic inhibitors targeting components of the PI3K pathway are actively being developed as therapeutics for the treatment of inflammatory disorders and cancer. These targeted drugs inhibit the activity of either PI3K itself or downstream protein kinases. However, a previously unexplored, alternate strategy is to activate the negative regulatory phosphatases in this pathway. The SH2-containing inositol-5'-phosphatase SHIP1 is a normal physiologic counter-regulator of PI3K in immune/hematopoietic cells that hydrolyzes the PI3K product phosphatidylinositiol-3,4,5-trisphosphate (PIPS). We now describe the identification and characterization of potent and specific small-molecule activators of SHIP1. These compounds represent the first small-molecule activators of a phosphatase, and are able to activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 cells. Mechanism of activation studies with these compounds suggest that they bind a previously undescribed, allosteric activation domain within SHIP1. Furthermore, in vivo administration of these compounds was protective in mouse models of endotoxemia and acute cutaneous anaphylaxis, suggesting that SHIP1 agonists could be used therapeutically to inhibit the PI3K pathway. activity in intact macrophage and mast