The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities
The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities
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DOI：
10.1248/bpb.b17-00902
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发表时间：
2018-04-01
影响因子：
2
通讯作者：
Fujita, Mikako
中科院分区：
文献类型：
--
作者：
Ciftci, Halil Ibrahim;Ozturk, Safiye Emirdag;Fujita, Mikako
嵌合酪氨酸激酶断点簇区激酶-阿贝尔森激酶（BCR-ABL）靶向药物伊马替尼的发现从概念上改变了慢性髓性白血病（CML）的治疗。然而，一些CML患者表现出对伊马替尼的耐药性。为了解决这一问题，一些人工杂环化合物已被确定为BCR-ABL抑制剂。在这里，我们研究了植物来源的五环三萜石膏原素和/或它们的衍生物是否对BCR-ABL具有抑制活性。其中，3-羟基-23-oxoolean-12-en-28-oate （1c）对CML细胞系K562最有效，IC50值为9.3 μ m，而对正常外周血单核细胞的IC50值为276.0 μ m，选择性优于伊马替尼。化合物1c对BCR-ABL的激酶组分Abelson激酶1 （ABLI）具有体外抑制活性（IC50=8.7 μ m）。此外，与伊马替尼相比，化合物1c对8种激酶表现出不同的抑制特征。通过分子对接研究ABL与lc的ATP结合位点之间的相互作用，其结合方式不同于伊马替尼及新一代抑制剂。此外，1c抑制BCR-ABL下游的信号传导。这项研究表明，植物提取物可能是CML治疗的一个来源，并提供了一种克服已知BCR-ABL抑制剂耐药性的策略。
The discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC50 value of 9.3 mu m. In contrast, the IC50 against normal peripheral blood mononuclear cells was 276.0 mu m, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABLI) (IC50=8.7 mu m), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and lc was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppressed signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors.