Targeting phosphoinositide 3-kinase - Moving towards therapy
Targeting phosphoinositide 3-kinase - Moving towards therapy
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DOI：
10.1016/j.bbapap.2007.10.003
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发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Wymann, Matthias P.
中科院分区：
文献类型：
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作者：
Marone, Romina;Cmijanovic, Vladimir;Wymann, Matthias P.
磷酸肌醇3-激酶（PI 3 K）协调细胞反应，包括促有丝分裂信号传导、细胞存活和生长、代谢控制、囊泡运输、脱粒、细胞骨架重排和迁移。通过激活生长因子受体或编码PI 3 K β的PlK 3CA基因座中的突变、通过在染色体10中缺失的脂质磷酸酶和张力蛋白同源物（PTEN/MMAC/TEP 1）的功能丧失、通过蛋白激酶B（PK B/Akt）的上调或结节性硬化症复合体（TSC 1/2）的损伤，发生PI 3 K途径的失调。所有这些事件都与生长和增殖有关，因此引起了人们对癌症中PI 3 K通路的药物靶向的极大兴趣。小鼠中PI 3 K γ（p110 γ）和PI 3 K δ（p110 δ）的遗传靶向强调了这些PI 3 K亚型在炎症和过敏中的中心作用，因为它们调节白细胞的趋化性和肥大细胞的脱粒。对PI 3 K γ具有选择性的概念验证分子已经成功地缓解了类风湿性关节炎和红斑狼疮小鼠模型中的疾病进展。随着靶向PI 3 K向慢性非致命性疾病的治疗进展，PI 3 K抑制剂的安全性问题增加。目前的许多抑制剂系列干扰雷帕霉素（TOR）、DNA依赖性蛋白激酶（DNA-PKc）和共济失调毛细血管扩张症突变基因产物（ATM）的活性。在这里，我们回顾了目前的疾病相关知识的亚型特异性PI 3 K在上述疾病中的功能，并回顾了超过400个最近的专利，涵盖药物靶向PI 3 K的进展。目前，靶向PI 3 K通路的几种药物已进入实体瘤和心肌梗死后组织损伤抑制（I、II期）的临床试验（I期）。(C)2007 Elsevier B. V.保留所有权利。
Phosphoinositide 3-kinases (PI3K) orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskeletal rearrangement and migration. Deregulation of the PI3K pathway occurs by activating mutations in growth factor receptors or the PlK3CA locus coding for PI3K(x, by loss of function of the lipid phosphatase and tensin homolog deleted in chromosome ten (PTEN/MMAC/TEP1), by the up-regulation of protein kinase B (PKB/Akt), or the impairment of the tuberous sclerosis complex (TSC1/2). All these events are linked to growth and proliferation, and have thus prompted a significant interest in the pharmaceutical targeting of the PI3K pathway in cancer. Genetic targeting of PI3K gamma (p110 gamma) and PI3K delta (p110 delta) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy, as they modulate chemotaxis of leukocytes and degranulation in mast cells. Proof-of-concept molecules selective for PI3K gamma have already successfully alleviated disease progress in murine models of rheumatoid arthritis and lupus erythematosus. As targeting PI3K moves forward to therapy of chronic, non-fatal disease, safety concerns for PI3K inhibitors increase. Many of the present inhibitor series interfere with target of rapamycin (TOR), DNA-dependent protein kinase (DNA-PKc,) and activity of the ataxia telangiectasia mutated gene product (ATM). Here we review the current disease-relevant knowledge for isoform-specific PI3K function in the above mentioned diseases, and review the progress of >400 recent patents covering pharmaceutical targeting of PI3K. Currently, several drugs targeting the PI3K pathway have entered clinical trials (phase 1) for solid tumors and suppression of tissue damage after myocardial infarction (phases I,II). (C) 2007 Elsevier B.V. All rights reserved.