Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies.
Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies.
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DOI：
10.3389/fimmu.2012.00256
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发表时间：
2012
影响因子：
7.3
通讯作者：
Gold MR
中科院分区：
文献类型：
--
作者：
Puri KD;Gold MR
磷酸肌肽3-激酶p110催化亚基（p110δ）的δ异构体主要在造血细胞中表达，在b细胞的发育和功能中起重要作用。利用缺乏功能性p110δ蛋白的小鼠以及使用高选择性p110δ化学抑制剂的研究表明，通过含有p110δ的PI3K复合物（PI3Kδ）的信号传导对B细胞存活、迁移和激活至关重要，它在B细胞上的关键受体下游发挥作用，包括B细胞抗原受体、趋化因子受体、促生存受体（如bif - r和IL-4受体）。和共刺激受体，如CD40和toll样受体（TLRs）。同样，这种PI3K亚型在b细胞淋巴瘤的存活、增殖和传播中起着关键作用。本文总结了p110δ酶活性的小分子抑制剂可以在体外和体内抑制这些过程的研究，并且这些p110δ抑制剂在治疗多种b细胞恶性肿瘤（包括慢性淋巴细胞白血病（CLL）和非霍奇金淋巴瘤（NHL））的临床试验中显示出疗效。PI3Kδ还在自身反应性B细胞的激活、增殖和组织归巢中发挥关键作用，这些B细胞有助于自身免疫性疾病，特别是先天样B细胞群，如边缘区（MZ） B细胞和与自身免疫密切相关的B-1细胞。我们讨论了p110δ抑制剂的潜在效用，无论是单独或联合b细胞消耗，治疗自身免疫性疾病，如狼疮，类风湿性关节炎和1型糖尿病。由于PI3Kδ在b细胞介导的自身免疫性炎症和b细胞恶性肿瘤中起主要作用，PI3Kδ抑制剂可能是治疗这些疾病的一种有希望的治疗方法。
The delta isoform of the p110 catalytic subunit (p110δ) of phosphoinositide 3-kinase is expressed primarily in hematopoietic cells and plays an essential role in B-cell development and function. Studies employing mice lacking a functional p110δ protein, as well as the use of highly-selective chemical inhibitors of p110δ, have revealed that signaling via p110δ-containing PI3K complexes (PI3Kδ) is critical for B-cell survival, migration, and activation, functioning downstream of key receptors on B cells including the B-cell antigen receptor, chemokine receptors, pro-survival receptors such as BAFF-R and the IL-4 receptor, and co-stimulatory receptors such as CD40 and Toll-like receptors (TLRs). Similarly, this PI3K isoform plays a key role in the survival, proliferation, and dissemination of B-cell lymphomas. Herein we summarize studies showing that these processes can be inhibited in vitro and in vivo by small molecule inhibitors of p110δ enzymatic activity, and that these p110δ inhibitors have shown efficacy in clinical trials for the treatment of several types of B-cell malignancies including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). PI3Kδ also plays a critical role in the activation, proliferation, and tissue homing of self-reactive B cells that contribute to autoimmune diseases, in particular innate-like B-cell populations such as marginal zone (MZ) B cells and B-1 cells that have been strongly linked to autoimmunity. We discuss the potential utility of p110δ inhibitors, either alone or in combination with B-cell depletion, for treating autoimmune diseases such as lupus, rheumatoid arthritis, and type 1 diabetes. Because PI3Kδ plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, PI3Kδ inhibitors may represent a promising therapeutic approach for treating these diseases.