Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2.
Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2.
复制标题
谷氨酰胺转运蛋白 ASCT2 的苄基脯氨酸衍生抑制剂的结构活性关系。
DOI：
10.1016/j.bmcl.2016.12.063
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发表时间：
2017
影响因子：
2.7
通讯作者：
Grewer,Christof
中科院分区：
文献类型：
--
作者：
Singh,Kurnvir;Tanui,Rose;Gameiro,Armanda;Eisenberg,Gilad;Colas,Claire;Schlessinger,Avner;Grewer,Christof
谷氨酰胺转运蛋白ASCT2已被鉴定为抑制癌细胞快速生长的有希望的靶点。然而，ASCT2药理学尚未完全确立。本文对一系列取代苄基脯氨酸衍生物进行了系统的构效分析。苯环上的取代产生具有ASCT2抑制剂特征的化合物。表观结合亲和力随着侧链疏水性的增加而增加。相反，未观察到ASCT2结合位点与苯环上特定位置的相互作用。最有效的化合物抑制ASCT2阴离子电导，aKi为3 μM，这与其他人最近报道的更大体积和更高分子量的抑制剂的范围相同。实验结果与基于抑制剂对ASCT2同源性模型的对接的计算分析一致。苄基脯氨酸支架为进一步提高未来ASCT2抑制剂的结合效力提供了有价值的工具。
The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with aKiof 3 μM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors.