Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Göteborg, Sweden.
J Med Chem. 2012 May 24;55(10):4872-6. doi: 10.1021/jm3003944. Epub 2012 May 16.
A series of 3-substituted-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amines have been designed, synthesized, and evaluated as RET protein kinase inhibitors. On the basis of docking results, a small library of pyrazolopyrimidine compounds with an extended hydrophobic side arm was synthesized. The most promising of the compounds (7a) displayed efficient inhibition in vitro and good selectivity when tested on a panel of kinases. Furthermore, 7a inhibited GDNF-induced RET phosphorylation of ERK1/2 in MCF-7 breast cancer cells at concentrations as low as 100 nM.
已经设计、合成并评价了一系列 3-取代-1-异丙基-1H-吡唑并[3,4-d]嘧啶-4-胺，作为 RET 蛋白激酶抑制剂。基于对接结果，合成了具有扩展疏水性侧臂的吡唑并嘧啶化合物的小文库。在所测试的激酶中，最有前途的化合物 (7a) 在体外表现出有效的抑制作用和良好的选择性。此外，化合物 7a 在低至 100 nM 的浓度下抑制 MCF-7 乳腺癌细胞中 GDNF 诱导的 RET 磷酸化 ERK1/2。
