免疫细胞PI3K p110δ和p110γ双重抑制剂的发现：新型抗炎药物的原型
Discovery of dual inhibitors of the immune cell PI3Ks p110delta and p110gamma: a prototype for new anti-inflammatory drugs.
作者信息
Williams Olusegun, Houseman Benjamin T, Kunkel Eric J, Aizenstein Brian, Hoffman Randy, Knight Zachary A, Shokat Kevan M
机构信息
Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, San Francisco, CA 94158, USA.
出版信息
Chem Biol. 2010 Feb 26;17(2):123-34. doi: 10.1016/j.chembiol.2010.01.010.
Abstract
PI3Kdelta and PI3Kgamma regulate immune cell signaling, while the related PI3Kalpha and PI3Kbeta regulate cell survival and metabolism. Selective inhibitors of PI3Kdelta/gamma represent a potential class of anti-inflammatory agents lacking the antiproliferative effects associated with PI3Kalpha/beta inhibition. Here we report the discovery of PI3Kdelta/gamma inhibitors that display up to 1000-fold selectivity over PI3Kalpha/beta and evaluate these compounds in a high-content inflammation assay using mixtures of primary human cells. We find selective inhibition of only PI3Kdelta is weakly anti-inflammatory, but PI3Kdelta/gamma inhibitors show superior inflammatory marker suppression through suppression of lipopolysaccharide-induced TNFalpha production and T cell activation. Moreover, PI3Kdelta/gamma inhibition yields an anti-inflammatory signature distinct from pan-PI3K inhibition and known anti-inflammatory drugs, yet bears striking similarities to glucocorticoid receptor agonists. These results highlight the potential of selectively designing drugs that target kinases with shared biological function.
摘要
PI3Kδ和PI3Kγ调节免疫细胞信号传导，而相关的PI3Kα和PI3Kβ调节细胞存活和代谢。PI3Kδ/γ的选择性抑制剂代表了一类潜在的抗炎剂，缺乏与PI3Kα/β抑制相关的抗增殖作用。在此我们报告了PI3Kδ/γ抑制剂的发现，其对PI3Kα/β的选择性高达1000倍，并使用原代人类细胞混合物在高内涵炎症测定中评估了这些化合物。我们发现仅选择性抑制PI3Kδ具有较弱的抗炎作用，但PI3Kδ/γ抑制剂通过抑制脂多糖诱导的TNFα产生和T细胞活化表现出卓越的炎症标志物抑制作用。此外，PI3Kδ/γ抑制产生了一种不同于泛PI3K抑制和已知抗炎药物的抗炎特征，但与糖皮质激素受体激动剂具有显著相似性。这些结果突出了选择性设计靶向具有共同生物学功能激酶的药物的潜力。
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Nat Chem Biol. 2010 Mar;6(3):244. doi: 10.1038/nchembio0310-244b.
2
Amlodipine inhibits TNF-alpha production and attenuates cardiac dysfunction induced by lipopolysaccharide involving PI3K/Akt pathway.氨氯地平通过 PI3K/Akt 通路抑制脂多糖诱导的 TNF-α 产生并减轻心脏功能障碍。
Int Immunopharmacol. 2009 Aug;9(9):1032-41. doi: 10.1016/j.intimp.2009.04.010. Epub 2009 Apr 23.
3
Phosphoinositide 3-kinases gamma and delta, linkers of coordinate C5a receptor-Fcgamma receptor activation and immune complex-induced inflammation.磷酸肌醇3激酶γ和δ，协同C5a受体 - Fcγ受体激活及免疫复合物诱导炎症的连接分子。
J Biol Chem. 2008 Nov 28;283(48):33296-303. doi: 10.1074/jbc.M804617200. Epub 2008 Sep 11.
4
PI3Kgamma (PI3Kgamma) is essential for efficient induction of CXCR3 on activated T cells.磷脂酰肌醇-3激酶γ（PI3Kγ）对于在活化T细胞上高效诱导CXC趋化因子受体3（CXCR3）至关重要。
Blood. 2008 Oct 15;112(8):3048-51. doi: 10.1182/blood-2008-02-135715. Epub 2008 Jul 24.
5
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J Immunol. 2008 Jun 15;180(12):7980-8. doi: 10.4049/jimmunol.180.12.7980.
6
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Pharmacol Ther. 2008 May;118(2):192-205. doi: 10.1016/j.pharmthera.2008.02.004. Epub 2008 Mar 5.
7
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J Immunol. 2008 Feb 15;180(4):2538-44. doi: 10.4049/jimmunol.180.4.2538.
8
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9
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