Design, synthesis, biological evaluation and molecular modeling of novel 1H-pyrazolo[3,4-d]pyrimidine derivatives as BRAFV600E and VEGFR-2 dual inhibitors
Design, synthesis, biological evaluation and molecular modeling of novel 1H-pyrazolo[3,4-d]pyrimidine derivatives as BRAFV600E and VEGFR-2 dual inhibitors
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作为 BRAFV600E 和 VEGFR-2 双重抑制剂的新型 1H-吡唑并[3,4-d]嘧啶衍生物的设计、合成、生物学评价和分子建模
DOI：
10.1016/j.ejmech.2018.05.054
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Wu X
中科院分区：
文献类型：
--
作者：
Wang Y;Wan S;Li Z;Fu Y;Wang G;Zhang J;Wu X
Aiming to explore novel BRAFV600Eand VEGFR-2 dual inhibitors, a series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed, synthesized and biologically evaluated in this study. Most of the synthesized 1H-pyrazolo[3,4-d]pyrimidine compounds displayed moderate to high potent activity in both enzymatic and cellular proliferation assays. Among these compounds,9e,9g,9mand9ushowed remarkably high inhibitory activities against both BRAFV600Eand VEGFR-2 kinase comparable to positive control Sorafenib. Particularly, compound9ualso showed potent anti-proliferative activity against BRAFV600E-expressing A375 (IC50= 1.74 μM) and H-29 (IC50= 6.92 μM) as well as VEGFR-2-expressing HUVEC (IC50= 5.89 μM), which was also comparable to Sorafenib. Furthermore, kinase selectivity profile showed that9uhad almost poor or no significant inhibitory activity against wild-type BRAF and 15 other tested protein kinases. Flow cytometric analysis showed that compound9umainly arrested the A375 and HUVEC cell lines in the G0/G1stage with a concentration-dependent effect. In addition, the molecular docking and molecular dynamics simulations suggested that9uadopted a similar binding pattern with Sorafenib at the ATP-binding sites of BRAFV600Eand VEGFR-2. Taken together, these results indicated that compound9umay serve as novel lead compound in research on more effective BRAFV600Eand VEGFR-2 dual inhibitors.
