Zaytsev Andrey, Dodd Barry, Magnani Matteo, Ghiron Chiara, Golding Bernard T, Griffin Roger J, Liu Junfeng, Lu Xiaohong, Micco Iolanda, Newell David R, Padova Alessandro, Robertson Graeme, Lunec John, Hardcastle Ian R
Newcastle Cancer Centre, Northern Institute for Cancer Research and School of Chemistry, Newcastle University, Bedson Building, Newcastle upon Tyne, NE1 7RU, UK.
Siena Biotech S.p.A., Strada del Petriccio e Belriguardo 35, Siena, 53100, Italy.
Chem Biol Drug Des. 2015 Aug;86(2):180-9. doi: 10.1111/cbdd.12474. Epub 2014 Dec 19.
Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.
基于已报道的MDM2-p53抑制剂，采用“骨架跃迁”方法设计了两个取代苯并咪唑文库。在文库枚举并对接至MDM2 X射线结构后选择取代基。使用高效的溶液相方法制备苯并咪唑文库，并筛选其对MDM2-p53和MDMX-p53蛋白质-蛋白质相互作用的抑制作用。关键实例显示对两个靶点均具有抑制活性。
