State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
Curr Med Chem. 2012;19(6):871-92. doi: 10.2174/092986712799034923.
Chemical space is defined as all possible small organic molecules, including those present in biological systems, which is so vast that so far only a tiny fraction of it has been explored. Indeed, a thorough examination of all "chemical space" is practically impossible. The success of three EGFR inhibitors (Gefitnib, Erlotinib, Lapatinib) suggests that 4-anilinoquinazoline scaffold is still worth developing in the future. To date hundreds of this sort of derivatives have been synthesized and show potent anticancer activities. Most of the compounds have been proved to be EGFR/HER2 kinase inhibitors, binding at the hinge region of the ATP site and some lead compounds have been optimized against a number of different kinases, including VEGFR-2, Src, Aurora A/B, Tpl, Clk and PDE10A. Now there is now a rich pipeline of novel anticancer agents based on 4-anilinoquinazoline in early phase clinical trials. This review will highlight the exploration of chemical space of 4-anilinoquinazoline in the past ten years and we hope that increasing knowledge of the SAR and cellular processes underlying the antitumor-activity of anilinoquinazoline derivatives will be beneficial to the rational design of new generation of small molecule anticancer drugs.
化学空间被定义为所有可能的小分子有机化合物，包括存在于生物系统中的化合物，其范围如此之广，以至于到目前为止，我们只探索了其中的一小部分。事实上，对所有“化学空间”进行彻底的考察在实际上是不可能的。三个 EGFR 抑制剂（吉非替尼、厄洛替尼、拉帕替尼）的成功表明，4-苯胺喹唑啉支架在未来仍然值得进一步开发。迄今为止，已经合成了数百种此类衍生物，并显示出很强的抗癌活性。大多数化合物已被证明是 EGFR/HER2 激酶抑制剂，与 ATP 结合位点的铰链区结合，一些先导化合物已针对多种不同的激酶进行了优化，包括 VEGFR-2、Src、Aurora A/B、Tpl、Clk 和 PDE10A。现在，有许多基于 4-苯胺喹唑啉的新型抗癌药物正在进行早期临床试验。本综述将重点介绍过去十年中对 4-苯胺喹唑啉化学空间的探索，我们希望增加对苯胺喹唑啉衍生物抗肿瘤活性的 SAR 和细胞过程的了解，将有助于新一代小分子抗癌药物的合理设计。
