High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of rnultidrug resistance protein 4 (MRP4)
High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of rnultidrug resistance protein 4 (MRP4)
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DOI：
10.1016/j.bcp.2014.05.023
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发表时间：
2014-09-01
影响因子：
5.8
通讯作者：
Norris, Murray D.
中科院分区：
文献类型：
--
作者：
Cheung, Leanna;Flemming, Claudia L.;Norris, Murray D.
多药耐药蛋白4（MRP 4/ABCC 4）是ATP结合盒转运蛋白超家族的成员，是一种有机阴离子转运蛋白，能转运多种重要的信号分子和药物。有人提议，MRP 4有助于在健康和疾病方面发挥许多功能;然而，在大多数情况下，这些联系仍有待明确确立。了解MRP 4的生理和药理作用的主要限制是缺乏特异性小分子抑制剂，大多数已建立的抑制剂也靶向其他ABC转运蛋白家族成员，或抑制重要MRP 4底物的产生、功能或降解。因此，我们着手确定更具选择性和耐受性良好的MRP 4抑制剂，可用于研究这种转运蛋白的许多拟议功能。使用高通量筛选，我们确定了两种化学上不同的小分子，Ceefourin 1和Ceefourin 2，它们抑制多种MRP 4底物的转运，但对MRP 4的选择性高于其他ABC转运蛋白，包括P-糖蛋白（P-gp），ABCG 2（乳腺癌耐药蛋白; BCRP）和MRP 1（多药耐药蛋白1; ABCC 1）。在细胞试验中，这两种化合物都是比最广泛使用的抑制剂MK-571更有效的MRP 4抑制剂，需要更低的浓度才能达到相当的抑制水平。此外，Ceefourin 1和Ceefourin 2具有低细胞毒性和高微粒体和酸稳定性。这些新发现的抑制剂对于更好地理解MRP 4的生物学作用具有重要价值，并且可能代表具有治疗应用的化合物类别。(C)2014爱思唯尔公司All rights reserved.
Multidrug resistance protein 4 (MRP4/ABCC4), a member of the ATP-binding cassette (ABC) transporter superfamily, is an organic anion transporter capable of effluxing a wide range of physiologically important signalling molecules and drugs. MRP4 has been proposed to contribute to numerous functions in both health and disease; however, in most cases these links remain to be unequivocally established. A major limitation to understanding the physiological and pharmacological roles of MRP4 has been the absence of specific small molecule inhibitors, with the majority of established inhibitors also targeting other ABC transporter family members, or inhibiting the production, function or degradation of important MRP4 substrates. We therefore set out to identify more selective and well tolerated inhibitors of MRP4 that might be used to study the many proposed functions of this transporter. Using high-throughput screening, we identified two chemically distinct small molecules, Ceefourin 1 and Ceefourin 2, that inhibit transport of a broad range of MRP4 substrates, yet are highly selective for MRP4 over other ABC transporters, including P-glycoprotein (P-gp), ABCG2 (Breast Cancer Resistance Protein; BCRP) and MRP1 (multidrug resistance protein 1; ABCC1). Both compounds are more potent MRP4 inhibitors in cellular assays than the most widely used inhibitor, MK-571, requiring lower concentrations to effect a comparable level of inhibition. Furthermore, Ceefourin 1 and Ceefourin 2 have low cellular toxicity, and high microsomal and acid stability. These newly identified inhibitors should be of great value for efforts to better understand the biological roles of MRP4, and may represent classes of compounds with therapeutic application. (C) 2014 Elsevier Inc. All rights reserved.