Ishikawa Toshihisa, Saito Hikaru, Hirano Hiroyuki, Inoue Yutaka, Ikegami Yoji
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan.
Methods Mol Biol. 2012;910:267-78. doi: 10.1007/978-1-61779-965-5_11.
Human ATP-binding cassette (ABC) transporter ABCG2 (BCRP) is critically involved in multidrug resistance of human cancer. This transporter exhibits broad substrate specificity toward structurally diverse compounds, as do other ABC transporters, such as ABCB1 (P-glycoprotein/MDR1), ABCC1 (MRP1/GS-X pump), and ABCC2 (MRP2/cMOAT). To gain insight into the relationship between the molecular structure of compounds and the ABCG2-mediated transport activity, we have developed a high-speed screening method to analyze the substrate specificity of ABCG2. In addition, we have developed an algorithm that analyzes QSAR to evaluate ABCG2-drug interactions. This chapter presents our strategy of transport mechanism-based molecular design to circumvent multidrug resistance of cancer.
人类ATP结合盒（ABC）转运蛋白ABCG2（乳腺癌耐药蛋白，BCRP）在人类癌症的多药耐药中起关键作用。与其他ABC转运蛋白，如ABCB1（P-糖蛋白/多药耐药蛋白1，MDR1）、ABCC1（多药耐药相关蛋白1/谷胱甘肽-S-转移酶-X泵，MRP1/GS-X pump）和ABCC2（多药耐药相关蛋白2/胆小管多特异性有机阴离子转运体，MRP2/cMOAT）一样，该转运蛋白对结构多样的化合物表现出广泛的底物特异性。为深入了解化合物的分子结构与ABCG2介导的转运活性之间的关系，我们开发了一种高速筛选方法来分析ABCG2的底物特异性。此外，我们还开发了一种算法来分析定量构效关系（QSAR），以评估ABCG2与药物的相互作用。本章介绍了我们基于转运机制的分子设计策略，以规避癌症的多药耐药性。
