Institute of Pharmacy, Christian-Albrechts-University of Kiel , Gutenbergstraße 76, D-24116 Kiel, Germany.
J Med Chem. 2015 Jan 8;58(1):170-82. doi: 10.1021/jm500373x. Epub 2014 Jul 21.
In this study we report on the hit optimization of substituted 3,5-diaryl-pyrazin-2(1H)-ones toward potent and effective platelet-derived growth factor receptor (PDGF-R) β-inhibitors. Originally, the 3,5-diaryl-pyrazin-2-one core was derived from the marine sponge alkaloid family of hamacanthins. In our first series compound 2 was discovered as a promising hit showing strong activity against PDGF-Rβ in the kinase assay (IC50 = 0.5 μM). Furthermore, 2 was shown to be selective for PDGF-Rβ in a panel of 24 therapeutically relevant protein kinases. Molecular modeling studies on a PDGF-Rβ homology model using prediction of water thermodynamics suggested an optimization strategy for the 3,5-diaryl-pyrazin-2-ones as DFG-in binders by using a phenolic OH function to replace a structural water molecule in the ATP binding site. Indeed, we identified compound 38 as a highly potent inhibitor with an IC50 value of 0.02 μM in a PDGF-Rβ enzymatic assay also showing activity against PDGF-R dependent cancer cells.
在这项研究中，我们报告了取代的 3,5-二芳基-吡嗪-2(1H)-酮向有效和有效的血小板衍生生长因子受体 (PDGF-R)β-抑制剂的命中优化。最初，3,5-二芳基-吡嗪-2-酮核心源自海洋海绵生物碱家族的哈马亭。在我们的第一个系列化合物 2 被发现为一个很有前途的命中，在激酶测定中表现出对 PDGF-Rβ 的强烈活性（IC50 = 0.5 μM）。此外，在 24 种治疗相关蛋白激酶的面板中，2 被证明对 PDGF-Rβ 具有选择性。使用预测水热力学的 PDGF-Rβ 同源模型的分子建模研究表明，DFG-in 结合物的优化策略是使用酚羟基功能取代 ATP 结合位点中的结构水分子。事实上，我们鉴定出化合物 38 是一种高度有效的抑制剂，在 PDGF-Rβ 酶测定中的 IC50 值为 0.02 μM，对 PDGF-R 依赖性癌细胞也表现出活性。
