Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, 72074 Tuebingen, Germany.
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, University of Tuebingen, 72076 Tuebingen, Germany.
Cells. 2022 Apr 12;11(8):1299. doi: 10.3390/cells11081299.
Small-molecule protein kinase inhibitors are used for the treatment of cancer, but off-target effects hinder their clinical use. Especially off-target activation of the pregnane X receptor (PXR) has to be considered, as it not only governs drug metabolism and elimination, but also can promote tumor growth and cancer drug resistance. Consequently, PXR antagonism has been proposed for improving cancer drug therapy. Here we aimed to identify small-molecule kinase inhibitors of the Tübingen Kinase Inhibitor Collection (TüKIC) compound library that would act also as PXR antagonists. By a combination of in silico screen and confirmatory cellular reporter gene assays, we identified four novel PXR antagonists and a structurally related agonist with a common phenylaminobenzosuberone scaffold. Further characterization using biochemical ligand binding and cellular protein interaction assays classified the novel compounds as mixed competitive/noncompetitive, passive antagonists, which bind PXR directly and disrupt its interaction with coregulatory proteins. Expression analysis of prototypical PXR target genes ABCB1 and CYP3A4 in LS174T colorectal cancer cells and HepaRG hepatocytes revealed novel antagonists as selective receptor modulators, which showed gene- and tissue-specific effects. These results demonstrate the possibility of dual PXR and protein kinase inhibitors, which might represent added value in cancer therapy.
小分子蛋白激酶抑制剂被用于癌症的治疗，但它们的非靶点效应阻碍了其临床应用。特别需要考虑的是妊娠相关 X 受体（PXR）的非靶点激活，因为它不仅调节药物代谢和消除，还可以促进肿瘤生长和癌症耐药性。因此，已经提出了 PXR 拮抗作用以改善癌症药物治疗。在这里，我们旨在从图宾根激酶抑制剂库（TüKIC）化合物库中鉴定出也作为 PXR 拮抗剂的小分子激酶抑制剂。通过计算机筛选和确认的细胞报告基因测定的组合，我们鉴定出了四种新型 PXR 拮抗剂和一种具有共同的苯基氨基苯并二氢吡喃酮骨架的结构相关激动剂。使用生化配体结合和细胞蛋白相互作用测定的进一步特征分析将新型化合物分类为混合竞争性/非竞争性、被动拮抗剂，它们直接结合 PXR 并破坏其与共调节蛋白的相互作用。在 LS174T 结肠直肠癌细胞和 HepaRG 肝细胞中对典型的 PXR 靶基因 ABCB1 和 CYP3A4 的表达分析显示，新型拮抗剂作为选择性受体调节剂，具有基因和组织特异性作用。这些结果表明了双重 PXR 和蛋白激酶抑制剂的可能性，这可能在癌症治疗中具有附加价值。
