Shukla Suneet, Kouanda Abdul, Silverton Latoya, Talele Tanaji T, Ambudkar Suresh V
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH , Bethesda, Maryland 20892, United States.
Mol Pharm. 2014 Jul 7;11(7):2313-22. doi: 10.1021/mp400762h. Epub 2014 Jun 5.
Nilotinib (Tasigna) is a tyrosine kinase inhibitor approved by the FDA to treat chronic phase chronic myeloid leukemia patients. It is also a transport substrate of the ATP-binding cassette (ABC) drug efflux transporters ABCB1 (P-glycoprotein, P-gp) and ABCG2 (BCRP), which may have an effect on the pharmacokinetics and toxicity of this drug. The goal of this study was to identify pharmacophoric features of nilotinib in order to potentially develop specific inhibitors of BCR-ABL kinase with minimal interactions with ABC drug transporters. Three-dimensional pharmacophore modeling and quantitative structure-activity relationship (QSAR) studies were carried out on a series of nilotinib analogues to identify chemical features that contribute to inhibitory activity of nilotinib against BCR-ABL kinase activity, P-gp, and ABCG2. Twenty-five derivatives of nilotinib were synthesized and were then tested to measure their activity to inhibit BCR-ABL kinase and to inhibit the function of ABC drug transporters. A set of in vitro experiments including kinase activity and cell-based transport assays and photolabeling of P-gp and ABCG2 with a transport substrate, [(125)I]-iodoarylazido-prazosin (IAAP), were carried out in isolated membranes to evaluate the potency of the derivatives to inhibit the function of ABC drug transporters and BCR-ABL kinase. Sixteen, fourteen, and ten compounds were selected as QSAR data sets, respectively, to generate PHASE v3.1 pharmacophore models for BCR-ABL kinase, ABCG2, and P-gp inhibitors. The IC50 values of these derivatives against P-gp, ABCG2, or BCR-ABL kinase were used to generate pharmacophore features required for optimal interactions with these targets. A seven-point pharmacophore (AADDRRR) for BCR-ABL kinase inhibitory activity, a six-point pharmacophore (ADHRRR) for ABCG2 inhibitory activity, and a seven-point pharmacophore (AADDRRR) for P-gp inhibitory activity were generated. The derived models clearly demonstrate high predictive power for test sets of BCR-ABL, ABCG2, and P-gp inhibitors. In aggregate, these results should aid in the development of specific inhibitors of BCR-ABL kinase that exhibit no or minimal interaction with ABC drug transporters.
尼洛替尼（达希纳）是一种经美国食品药品监督管理局（FDA）批准用于治疗慢性期慢性髓性白血病患者的酪氨酸激酶抑制剂。它也是ATP结合盒（ABC）药物外排转运体ABCB1（P-糖蛋白，P-gp）和ABCG2（乳腺癌耐药蛋白，BCRP）的转运底物，这可能会对该药物的药代动力学和毒性产生影响。本研究的目的是确定尼洛替尼的药效团特征，以便有可能开发出与ABC药物转运体相互作用最小的BCR-ABL激酶特异性抑制剂。对一系列尼洛替尼类似物进行了三维药效团建模和定量构效关系（QSAR）研究，以确定有助于尼洛替尼抑制BCR-ABL激酶活性、P-gp和ABCG2的化学特征。合成了25种尼洛替尼衍生物，然后对其抑制BCR-ABL激酶活性和ABC药物转运体功能的活性进行了测试。在分离的膜中进行了一组体外实验，包括激酶活性和基于细胞的转运测定以及用转运底物[(125)I]-碘芳基叠氮基哌唑嗪（IAAP）对P-gp和ABCG2进行光标记，以评估衍生物抑制ABC药物转运体和BCR-ABL激酶功能的效力。分别选择16种、14种和10种化合物作为QSAR数据集，以生成针对BCR-ABL激酶、ABCG2和P-gp抑制剂的PHASE v3.1药效团模型。这些衍生物针对P-gp、ABCG2或BCR-ABL激酶的IC50值用于生成与这些靶点最佳相互作用所需的药效团特征。生成了用于BCR-ABL激酶抑制活性的七点药效团（AADDRRR）、用于ABCG2抑制活性的六点药效团（ADHRRR）和用于P-gp抑制活性的七点药效团（AADDRRR）。所推导的模型清楚地显示出对BCR-ABL、ABCG2和P-gp抑制剂测试集具有较高的预测能力。总体而言，这些结果应有助于开发与ABC药物转运体无相互作用或相互作用最小的BCR-ABL激酶特异性抑制剂。
