Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors
Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors
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探索 (S)-3-氨基吡咯烷作为发现新型 Abl 和 PI3K 双重抑制剂的潜在有趣支架
DOI：
10.1016/j.ejmech.2011.01.020
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发表时间：
2011-04-01
影响因子：
6.7
通讯作者：
Jiang, Yuyang
中科院分区：
文献类型：
--
作者：
Zhang, Cunlong;Tan, Chunyan;Jiang, Yuyang
基于文献报道的PI 3 K对Abl抑制的补偿作用以及Abl与PI 3 K抑制剂联合用药改善的临床前效果，通过支持向量机筛选工具鉴定了一系列带有（S）-3-氨基吡咯烷的新型骨架的化合物为Abl和PI 3 K双重抑制剂，随后对其进行了合成和测试。大多数化合物表现出对CML白血病细胞系K562的有希望的细胞毒性和对Abl和PI 3 K激酶的中度抑制。这些化合物在K562细胞系中不诱导凋亡，表明它们的细胞毒活性不太可能是由于其他已知的抗CML机制。分子对接研究进一步表明，化合物5 k可以与Abl和PI 3 K结合，但与Abl的结合较弱，这与其低的激酶抑制率相一致。这些加上文献报道的证据表明，我们的新化合物的有希望的细胞毒性作用可能是由于Abl和PI 3 K抑制的集体效应。(c)2011年Elsevier Masson SAS。All rights reserved.
Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3-aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screening tool, which were subsequently synthesized and tested. Most compounds demonstrated promising cytoxicity against a CML leukemia cell-line K562 and moderate inhibition against Abl and PI3K kinases. These compounds induced no apoptosis in K562 cell-line, suggesting that their cytotoxic activities are unlikely duo to other known anti-CML mechanisms. Molecular docking study further showed that the compound 5k could bind with both Abl and PI3K, but the weaker binding with Abl compared to Imatinib is consistent with its low kinase inhibitory rates. These plus literature-reported evidences suggest that the promising cytotoxic effect of our novel compounds might be due to the collective effect of Abl and PI3K inhibition. (c) 2011 Elsevier Masson SAS. All rights reserved.