The breast cancer resistance protein (BCRP/ABCG2) transporter mediates the efflux of numerous antineoplastic drugs, playing a central role in multidrug resistance related to cancer. The absence of successful clinical trials using specific ABCG2 inhibitors reveals the urge to identify new compounds to attend this critical demand. In this work, a series of 13 magnolol derivatives was tested as ABCG2 inhibitors. Only two compounds, derivatives and , showed partial and complete ABCG2 inhibitory effect, respectively. This inhibition was selective toward ABCG2, since none of the 13 compounds inhibited neither P-glycoprotein nor MRP1. Both inhibitors ( and ) were not transported by ABCG2 and demonstrated a low cytotoxic profile even at high concentrations (up to 100 µM). emerged as the most promising compound of the series, considering the ratio between cytotoxicity (IG) and ABCG2 inhibition potency (IC), showing a therapeutic ratio (TR) higher than observed for (10.5 1.6, respectively). This derivative showed a substrate-independent and a mixed type of inhibition. The effect of compound on the ABCG2 ATPase activity and thermostability revealed allosteric protein changes. This compound did not affect the expression levels of ABCG2 and increased the binding of the conformational-sensitive antibody 5D3. A docking study showed that did not share the same binding site with ABCG2 substrate mitoxantrone. Finally, could revert the chemoresistance to SN-38 mediated by ABCG2.

中文翻译：

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厚朴酚衍生物作为乳腺癌抗性蛋白 (BCRP/ABCG2) 的特异性非细胞毒性抑制剂

乳腺癌耐药蛋白（BCRP/ABCG2）转运蛋白介导多种抗肿瘤药物的流出，在与癌症相关的多药耐药性中发挥着核心作用。由于缺乏使用特定 ABCG2 抑制剂的成功临床试验，人们迫切需要寻找新的化合物来满足这一关键需求。在这项工作中，测试了一系列 13 种厚朴酚衍生物作为 ABCG2 抑制剂。只有两种化合物，衍生物和，分别表现出部分和完全的ABCG2抑制作用。这种抑制对 ABCG2 是选择性的，因为 13 种化合物中没有一种既不抑制 P-糖蛋白也不抑制 MRP1。两种抑制剂 ( 和 ) 均不被 ABCG2 转运，即使在高浓度（高达 100 µM）下也表现出较低的细胞毒性。考虑到细胞毒性 (IG) 和 ABCG2 抑制效力 (IC) 之间的比率，显示出治疗比率 (TR) 高于观察到的水平（分别为 10.5 1.6），成为该系列中最有前途的化合物。该衍生物表现出底物依赖性和混合型抑制。化合物对 ABCG2 ATP 酶活性和热稳定性的影响揭示了变构蛋白的变化。该化合物不影响 ABCG2 的表达水平，并增加构象敏感抗体 5D3 的结合。对接研究表明，其与 ABCG2 底物米托蒽醌不具有相同的结合位点。最后，可以恢复 ABCG2 介导的对 SN-38 的化疗耐药性。