PI3K inhibitors block PI3K catalytic activity

A variety of inhibitors capable of blocking the phosphoinositide kinase activity of PI3K have been developed. These inhibitors display differential selectivity and inhibit kinase activity of their substrates by distinct mechanisms. For example, the first-generation PI3K inhibitor wortmannin (Wymann et al. 1996) covalently and irreversibly binds all classes of PI3K enzymes, as well as other kinases including mTOR, at a residue critical for catalytic activity. Although wortmannin is precluded from in vivo and clinical use due to its toxicity, it has proven to be a useful tool for in vitro laboratory studies. Newer inhibitors, such as BEZ235, are currently being investigated in Phase I clinical trials. BEZ235 is a dual pan-class I PI3K/mTOR inhibitor that blocks kinase activity by binding competitively to the ATP-binding pocket of these enzymes (Serra et al. 2008, Maira et al. 2008). BGT226 (Chang et al. 2011) and XL765 (Prasad et al. 2011) also inhibits both PI3K class I enzymes and mTOR. Other inhibitors in clinical trials, such as BKM120 (Maira et al. 2012), GDC0941 (Folkes et al. 2008, Junttila et al. 2009) and XL147 (Chakrabarty et al. 2012), are specific for class I PI3Ks and exhibit no activity against mTOR. Current research aims to identify isoform-specific PI3K inhibitors. Small molecule inhibitors that selectively inhibit PIK3CA (p110alpha), e.g. PIK-75 and A66, were used to study the role of p110alpha in signaling and growth of tumor cells (Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012). The PIK3CB (p110beta) specific inhibitor TGX221 has been used in in vitro models of vascular injury (Jackson et al. 2005), and the TGX221 derivative KIN-193 has been shown to block AKT activity and tumor growth in mice with p110beta activation or PTEN loss (Ni et al. 2012). CAL-101 is a PIK3CD (p110delta) specific inhibitor that is being clinically investigated as a therapeutic for lymphoid malignancies (Herman et al. 2010). It is hoped that, in the future, more specific inhibitors, such as those targeting selective PI3K isoforms, will provide optimum treatment while minimizing unwanted side effects. For a recent review, please refer to Liu et al. 2009.

多种能够阻断PI3K磷脂酰肌醇激酶活性的抑制剂已被开发。这些抑制剂表现出不同的选择性，并通过不同的机制抑制其底物的激酶活性。例如，第一代PI3K抑制剂沃曼尼（Wymann et al. 1996）通过共价且不可逆地结合所有类别的PI3K酶，以及其他激酶包括mTOR，在催化活性至关重要的残基处。尽管沃曼尼因毒性问题无法用于体内及临床应用，但它已被证实是体外实验室研究的有用工具。新型的抑制剂，如BEZ235，目前正在I期临床试验中进行研究。BEZ235是一种双效广谱I类PI3K/mTOR抑制剂，通过竞争性地结合这些酶的ATP结合口袋来阻断激酶活性（Serra et al. 2008, Maira et al. 2008）。BGT226（Chang et al. 2011）和XL765（Prasad et al. 2011）也抑制I类PI3K酶和mTOR。其他处于临床试验阶段的抑制剂，如BKM120（Maira et al. 2012）、GDC0941（Folkes et al. 2008, Junttila et al. 2009）和XL147（Chakrabarty et al. 2012），对I类PI3K具有特异性，对mTOR无活性。当前研究旨在识别同型特异性PI3K抑制剂。选择性抑制PIK3CA（p110alpha）的小分子抑制剂，例如PIK-75和A66，被用于研究p110alpha在信号传导和肿瘤细胞生长中的作用（Knight et al. 2006, Sun et al. 2010, Jamieson et al. 2011, Utermark et al. 2012）。针对PIK3CB（p110beta）的特异性抑制剂TGX221被用于血管损伤的体外模型（Jackson et al. 2005），而TGX221衍生物KIN-193在p110beta激活或PTEN缺失的小鼠模型中显示出阻断AKT活性和抑制肿瘤生长的作用（Ni et al. 2012）。CAL-101是一种针对PIK3CD（p110delta）的特异性抑制剂，目前正在作为治疗淋巴瘤的临床试验药物进行研究（Herman et al. 2010）。人们希望，在未来，更多特异性的抑制剂，如针对选择性PI3K同型的抑制剂，能够在最大程度减少不期望的副作用的同时，提供最佳的治疗效果。欲了解更多近期综述，请参阅Liu et al. 2009。