Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 4, CH-8093 Zurich, Switzerland.
Department of Nuclear Medicine, University Hospital Zurich, CH-8091 Zurich, Switzerland.
J Med Chem. 2023 May 25;66(10):6782-6797. doi: 10.1021/acs.jmedchem.3c00168. Epub 2023 May 8.
Breast cancer resistance protein (BCRP, ABCG2) is an efflux transporter that plays a crucial role in multidrug resistance to antineoplastic drugs. Ko143, an analogue of the natural product fumitremorgin C, is a potent inhibitor of ABCG2 but is rapidly hydrolyzed to an inactive metabolite . To identify ABCG2 inhibitors with improved metabolic stability, we have assessed a series of Ko143 analogues for their ability to inhibit ABCG2-mediated transport in -transduced MDCK II cells and determined the stability of the most potent compounds in liver microsomes. The most promising analogues were evaluated by positron emission tomography. , three of the tested analogues were potent ABCG2 inhibitors and stable in microsomes. , they increased the distribution of the ABCG2/ABCB1 substrate [C]tariquidar to the brain both in wild-type (with Abcb1a/b transport blocked by tariquidar) and Abcb1a/b(-/-) mice. One analogue was more potent than Ko143 in both animal models.
乳腺癌耐药蛋白（BCRP，ABCG2）是一种外排转运蛋白，在多药耐药性抗恶性肿瘤药物中发挥着重要作用。Ko143 是天然产物 fumitremorgin C 的类似物，是 ABCG2 的有效抑制剂，但会迅速水解为无活性的代谢物。为了寻找代谢稳定性更好的 ABCG2 抑制剂，我们评估了一系列 Ko143 类似物抑制转染 MDCK II 细胞中 ABCG2 介导的转运的能力，并测定了最有效化合物在肝微粒体中的稳定性。最有前途的类似物通过正电子发射断层扫描进行了评估。结果，三种测试的类似物均为有效的 ABCG2 抑制剂，且在微粒体中稳定。这些类似物增加了 ABCG2/ABCB1 底物 [C]tariquidar 在野生型（阿霉素阻断 Abcb1a/b 转运）和 Abcb1a/b(-/-) 小鼠中的脑分布。一种类似物在两种动物模型中的活性均强于 Ko143。
