Bisarylureas Based on 1H-Pyrazolo[3,4-d]pyrimidine Scaffold as Novel Pan-RAF Inhibitors with Potent Anti-Proliferative Activities: Structure-Based Design, Synthesis, Biological Evaluation and Molecular Modelling Studies.
Bisarylureas Based on 1H-Pyrazolo[3,4-d]pyrimidine Scaffold as Novel Pan-RAF Inhibitors with Potent Anti-Proliferative Activities: Structure-Based Design, Synthesis, Biological Evaluation and Molecular Modelling Studies.
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基于 1H-吡唑并[3,4-d]嘧啶支架的双芳基脲作为具有有效抗增殖活性的新型泛 RAF 抑制剂：基于结构的设计、合成、生物学评价和分子建模研究
DOI：
10.3390/molecules22040542
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发表时间：
2017-03-29
期刊：
影响因子：
--
通讯作者：
Wu X
中科院分区：
文献类型：
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作者：
Fu Y;Wang Y;Wan S;Li Z;Wang G;Zhang J;Wu X
RAF(RAS激活因子)激酶是肿瘤治疗的重要靶点。为了寻找与天冬氨酸-苯丙氨酸-甘氨酸(Asp-Phe-Gly，DFG)运动产生的DFG-Out无效构象结合的RAF抑制剂，我们利用BRAF(v-RAF小鼠肉瘤病毒癌基因同源B1)的X射线共晶结构进行了基于结构的药物设计，从基于1H-吡唑并[3，4-d]嘧啶支架1a的双芳脲衍生物开始。大部分化合物对BRAFV600E具有良好的抑制活性，对四种肿瘤细胞(A375、HT-29、PC-3和A549)具有中到强的抗增殖活性，对癌细胞具有良好的选择性，而对正常细胞(Madin-Darby犬肾，MDCK)具有良好的选择性。最有希望的化合物1v不仅对BRAFV600E(半数抑制浓度，IC50=23.6 nM)有很强的抑制活性，而且对野生型BRAF(IC50=51.5 nM)和C-RAF(IC50=8.5 nM)也有很强的抑制活性，对A375、HT-29、PC-3和A549细胞具有有效的细胞抗增殖活性，并具有很好的选择性。此外，化合物1v主要使A375细胞停滞于G0/G1期，并对A375和HT-29细胞的MEK(丝裂原活化蛋白激酶)磷酸化有明显的抑制作用。综上所述，优化的化合物1v在体外表现出良好的PAN-RAF抑制剂活性。此外，通过分子动力学模拟和结合自由能计算进一步证实了化合物1v的前景。
RAF (Ras activating factor) kinases are important and attractive targets for cancer therapy. With the aim of discovering RAF inhibitors that bind to DFG-out inactive conformation created by the movement of Asp-Phe-Gly (DFG), we conducted structure-based drug design using the X-ray cocrystal structures of BRAF (v-raf murine sarcoma viral oncogene homolog B1), starting from bisarylurea derivative based on 1H-pyrazolo[3,4-d]pyrimidine scaffold 1a. Most of the synthesized compounds showed good to excellent inhibitory activities against BRAFV600E kinase, possessed moderate to potent anti-proliferative activities against four tumor cell lines (A375, HT-29, PC-3 and A549) and good selectivity towards cancer cells rather normal cells (Madin-Darby canine kidney, MDCK). The most promising compound, 1v, exhibited potent inhibitory activity against not only BRAFV600E (half maximal inhibitory concentration, IC50 = 23.6 nM) but also wild-type BRAF (IC50 = 51.5 nM) and C-RAF (IC50 = 8.5 nM), and effective cellular anti-proliferative activities against A375, HT-29, PC-3 and A549 cell lines as well as a very good selectivity profile. Moreover, compound 1v mainly arrested the A375 cell line in the G0/G1 stage, and showed significant suppression of MEK (mitogen-activated protein kinase kinase) phosphorylation in A375 and HT-29 cell lines. Taken together, the optimal compound 1v showed excellent in vitro potency as a pan-RAF inhibitor. In addition, the promise of compound 1v was further confirmed by molecular dynamics simulation and binding free energy calculations.
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影响因子：
11.2
作者：
Samowitz, WS;Sweeney, C;Slattery, ML
通讯作者：
Slattery, ML
影响因子：
10.3
作者：
Anforth, R. M.;Blumetti, T. C. M. P.;Fernandez-Penas, P.
通讯作者：
Fernandez-Penas, P.
影响因子：
14.8
作者：
Liu, Y;Gray, NS
通讯作者：
Gray, NS
影响因子：
5.5
作者：
Salomon-Ferrer, Romelia;Goetz, Andreas W.;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
64.8
作者：
通讯作者：
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