磷脂酰肌醇3-激酶抑制剂的研究进展。

Advances in development of phosphatidylinositol 3-kinase inhibitors.

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|核心内容：

磷脂酰肌醇3-激酶(PI3Ks)是一类磷脂酰肌醇3-激酶，它能使磷脂酰肌醇4，5-二磷酸(PIP2)在肌醇环的3-OH处磷酸化，生成磷脂酰肌醇3，4，5-三磷酸(PIP3)，进而激活Akt及其下游效应因子如mTOR，从而在细胞生长、存活等过程中发挥重要作用。

PI3K已经成为癌症治疗的重要药物靶点，因为在人类癌症中经常发现编码PI3Kalpha的PIK3CA的功能获得突变和PTEN的功能丧失突变。

近3年来，PI3K抑制剂的药物开发取得了突飞猛进的进展。

虽然PI3Kβ、δ和γ亚型特异性的PI3K抑制剂(TGX221、IC87114和AS-605240)已经被开发出来，分别用于治疗冠心病、哮喘和肾炎，但还没有有前途的PI3Kalpha特异性抑制剂。

相应地，几乎所有正在开发中的用于肿瘤治疗的PI3K抑制剂，如NVP-BEZ235、GDC-0941和ZSTK474，都是泛PI3K亚型抑制剂。

每种PAN-PI3K抑制剂似乎都能诱导共同的G1期阻滞。

所有这些药物都显示出良好的体内抗癌效果和低毒作用，因此大多数都进入了临床试验的评估阶段。

据报道，p-Akt和p-S6是监测这些药物疗效的可行的药效学生物标志物。

在发现这些和其他PI3K抑制剂的过程中，进行了详细的构效关系研究。

本文首先介绍了PI3K家族及其功能，然后综述了PI3K抑制剂的研究进展。

原文摘要：

Phosphatidylinositol 3-kinases (PI3Ks) are a class of lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate (PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which in turn activates Akt and the downstream effectors like mTOR, and therefore play important roles in cell growth, survival, etc. The phosphatase and tensin homolog deleted in chromosome ten (PTEN), acts as the catalytic antagonist of PI3K by dephosphorylating PIP3 to PIP2. PI3K has become an important drug target for cancer therapy, since gain-of-function mutations of PIK3CA encoding PI3Kalpha, as well as loss-of-function mutations of PTEN, have been frequently found in human cancers. The pharmaceutical development of PI3K inhibitors has made a great leap forward during the last 3 years. While PI3Kbeta, delta and gamma isoform-specific PI3K inhibitors (TGX-221, IC87114 and AS-605240) have been developed for therapy of coronary heart disease, asthma, and glomerulonephritis, respectively, a promising PI3Kalpha specific inhibitor is not yet available. Correspondingly, almost all of the promising PI3K inhibitors under development for caner therapy, such as NVP-BEZ235, GDC-0941 and ZSTK474, are pan-PI3K isoform inhibitors. Each of these pan-PI3K inhibitors seems to induce a common G1 phase arrest. All have shown favorable in vivo anticancer efficacies and low toxicities, and therefore most have entered evaluation in clinical trials. P-Akt and p-S6 have been reported to be feasible pharmacodynamic biomarkers for monitoring the efficacy of these agents. In the process of discovery of these and other PI3K inhibitors, detailed structure-activity relationship studies were carried out. This review summarizes key advances in the development of PI3K inhibitors, which is preceded by an introduction of PI3K family and their functions.

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参考文献：10.2174/092986709788803222

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