FS36作为新型人源Hsp90抑制剂的发现（英文）

Discovery of FS36 as a Novel Human Hsp90 Inhibitor

热休克蛋白90(Hsp90)通过对几百种蛋白质底物(客户蛋白质)进行合理的折叠、成熟其构象并且激活,在肿瘤细胞的生长和繁殖中发挥重要作用.因此,Hsp90成为非常有吸引力、有前途的抗肿瘤药物靶点,并且超过20种抑制剂已经进入临床实验阶段.我们在这里设计并合成了一个小分子抑制剂:FS36.收集了Hsp90~N-FS36复合物晶体结构的X射线衍射实验数据.高分辨率X射线晶体结构表明,FS36在ATP结合位点上与Hsp90~N相互作用,并且FS36可能替代核苷酸与Hsp90~N结合.FS36和Hsp90~N的复合物晶体结构和相互作用为后期设计和优化新型抗肿瘤药物奠定基础.

The heat shock protein 90（Hsp90） plays an important role in growth and progression of tumor cells through the appropriate folding, conformational maturation and activation of several hundred protein substrates（client proteins）. Thus, Hsp90 attracts a great many of interests as a promising target for antitumor drugs which results in more than 20 inhibitors advancing to clinical trials. Here,we designed and synthesized a small molecule inhibitor： FS36 and the X-ray diffraction data of the complex crystal of Hsp90~N-FS36 is collected. High-resolution X-ray crystallography shows that FS36 interacts with Hsp90~N at the ATP-binding pocket and this demonstrates that FS36 possibly substitutes nucleotides to bind to Hsp90~N. The complex crystal structure and the interactions between FS36 and Hsp90 Nlay the foundation of the design and majorization of novel antitumor drugs.