Braña Miguel F, Cacho Mónica, García M Luisa, Mayoral Elena P, López Berta, de Pascual-Teresa Beatriz, Ramos Ana, Acero Nuria, Llinares Francisco, Muñoz-Mingarro Dolores, Lozach Olivier, Meijer Laurent
Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, 28668-Boadilla del Monte, Madrid, Spain.
J Med Chem. 2005 Nov 3;48(22):6843-54. doi: 10.1021/jm058013g.
Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.
吡唑并哒嗪1a是由巴斯夫生物研究公司（马萨诸塞州伍斯特）进行的高通量筛选中鉴定出的一种有效的CDK1/细胞周期蛋白B抑制剂，并显示出对CDK家族具有选择性。已合成了先导化合物的类似物，并测试了它们的抗肿瘤活性。使用构象搜索和自动对接技术相结合的方法构建了先导化合物与CDK2 ATP结合位点之间复合物的分子模型。通过分子动力学模拟评估了所得复合物的稳定性，并根据化合物1a提出的结合模式对合成类似物获得的实验结果进行了合理化分析。作为构效关系研究的结果，单呋喃基化合物1o已被合成，并且是该系列中对CDK1活性最高的化合物之一。
