School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
Acta Pharmacol Sin. 2012 Dec;33(12):1441-58. doi: 10.1038/aps.2012.72. Epub 2012 Sep 17.
The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC(50), but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.
PI3K-Akt 通路是细胞增殖和存活的重要调节剂。在许多人类癌症类型中，包括结肠癌、乳腺癌、脑癌、肝癌、胃癌和肺癌，都报道了 PIK3CA 基因的改变导致 PI3K 激酶活性增强。PI3K 的失调导致 Akt 活性异常。因此，针对该通路可能对癌症治疗有影响。第一代 PI3K-Akt 抑制剂被证明具有高活性和低 IC（50），但后来发现它们具有毒性副作用和较差的药理学性质和选择性。因此，这些抑制剂仅在临床前模型中有效。然而，这些第一代抑制剂的衍生物更具选择性，并且在靶向 PI3K-Akt 通路方面非常有效，无论是单独使用还是联合使用。这些第二代抑制剂本质上是一种特定的化学部分，有助于与 PI3K/Akt 分子形成强氢键相互作用。本综述的目的是阐述目前在体外和体内抑制不同类型癌症中 PI3K 和 Akt 通路的各个组成部分所做的努力。我们这里的重点是这些新型疗法及其抑制作用，这些作用取决于它们的化学性质，以及它们向临床试验的发展。
