Garcia-Echeverria C, Sellers W R
Oncology Drug Discovery, Novartis Institutes for Biomedical Research, Basel, Switzerland.
Oncogene. 2008 Sep 18;27(41):5511-26. doi: 10.1038/onc.2008.246.
The abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been validated by epidemiological and experimental studies as an essential step toward the initiation and maintenance of human tumors. Notable in this regard are the prevalent somatic genetic alterations leading to the inactivation of the tumor suppressor gene PTEN and gain-of-function mutations targeting PIK3CA--the gene encoding the catalytic phosphosinositide-3 kinase subunit p110 alpha. A number of the intracellular components of this pathway have been targeted as anticancer drug discovery activities leading to the current panoply of clinical trials of inhibitors of PI3K, Akt and HSP90 in man. This review summarizes current preclinical knowledge of modulators of the PI3K/Akt pathway in which drug discovery and development activities have been advanced focusing on both the relevant clinical stage inhibitors and other disclosed tool compounds targeting PI3K, PDK1, Akt and HSP90.
流行病学和实验研究已证实，磷脂酰肌醇3激酶（PI3K）/Akt信号通路的异常激活是人类肿瘤发生和维持的关键步骤。在这方面值得注意的是，普遍存在的体细胞基因改变导致肿瘤抑制基因PTEN失活，以及针对PIK3CA的功能获得性突变——该基因编码催化性磷酸肌醇-3激酶亚基p110α。该信号通路的许多细胞内成分已成为抗癌药物研发的靶点，从而催生了目前针对PI3K、Akt和HSP90抑制剂开展的一系列人体临床试验。本综述总结了PI3K/Akt信号通路调节剂的当前临床前知识，其中药物研发活动已取得进展，重点关注相关临床阶段的抑制剂以及其他已披露的靶向PI3K、PDK1、Akt和HSP90的工具化合物。
