Institute of Drug Discovery and Development, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China.
Molecules. 2013 Jun 3;18(6):6491-503. doi: 10.3390/molecules18066491.
Over the years, the development of targeted medicines has made significant achievements. As a typical example, receptor tyrosine kinases (RTK) inhibitors have become important chemotherapy drugs for a variety of cancers. However, the effectiveness of these agents is always hindered by poor response rates and acquired drug resistance. In order to overcome these limitations, several dual-targeted inhibitors with quinazoline core were designed and synthesized. Though these compounds can simultaneously inhibit histone deacetylases (HDAC) as well as RTK, the structure-activity relationship (SAR) is still not clear enough. To further explore this type of dual-targeted inhibitors, a new class of quinazoline derivatives were designed and synthesized. Their activity evaluations include in vitro inhibitory activity of HDAC, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The SAR study indicated that the introduction of polar group such as hydroxamate on the 4-position of the quinazoline core is more likely to provide a potent HDACi/HER2i hybrid rather than HDACi/EGFRi molecule.
多年来，靶向药物的发展取得了重大成就。以受体酪氨酸激酶（RTK）抑制剂为例，它已成为多种癌症的重要化疗药物。然而，这些药物的疗效总是受到反应率低和获得性耐药性的限制。为了克服这些限制，设计并合成了几种以喹唑啉为核心的双靶点抑制剂。虽然这些化合物可以同时抑制组蛋白去乙酰化酶（HDAC）和 RTK，但结构-活性关系（SAR）还不够清楚。为了进一步探索这种双靶点抑制剂，设计并合成了一类新的喹唑啉衍生物。它们的活性评估包括对 HDAC、表皮生长因子受体（EGFR）和人表皮生长因子受体 2（HER2）的体外抑制活性。SAR 研究表明，在喹唑啉核心的 4 位引入羟肟酸等极性基团更有可能提供一种有效的 HDACi/HER2i 杂合体，而不是 HDACi/EGFRi 分子。
