Hsp90在肿瘤中的重要作用使其成为抗肿瘤药物的理想靶标，但其N端抑制剂存在诸多缺陷，寻找新的C端抑制剂成为目前研究的热点与前沿。前期研究中发现海洋真菌来源的一个骨架新颖的生物碱类化合物HDN636，具有显著的体内外抗肿瘤活性。初步研究发现HDN636可能作用在Hsp90的C端，且作用位点不同于其他已知抑制剂，提示HDN636可能为一个全新的Hsp90 C端抑制剂。本课题拟进一步研究HDN636与Hsp90的相互作用，明确其作用位点，并在分子、细胞、动物水平上研究HDN636对Hsp90功能的影响及分子机制，进而阐明其抗肿瘤作用机制。本研究将揭示一种全新的Hsp90抑制剂HDN636，为设计同类抑制剂提供分子模板；同时，Hsp90 C端新的作用位点的发现与功能阐明，也将为今后设计新型Hsp90抑制剂提供理论依据。本课题的实施，对于海洋微生物资源的综合利用、海洋创新药物的研制具有重要的意义。

The molecular chaperone Hsp90 (90 kDa heat-shock protein) is a remarkably versatile protein involved in tumor and has emerged as a promising target for the treatment of tumor. Inhibitors targeting the C-terminal domain of Hsp90 have been focused in the field of antitumor drug research, due to the various limitations of inhibitors targeting the N-terminal domain. Compound HDN636 is an alkaloid with novel skeleton produced from a marine fungus and has obvious antitumor activity both in vitro and in vivo. Further studies show that HDN636 possibly target a novel binding site in the C-terminal domain of Hsp90, which is different from that of the other inhibitors, indicating HDN636 is a unique Hsp90 inhibitor. In the future investigations, we will further confirm the interaction between HDN636 and Hsp90, and identify the novel binding site in Hsp90 molecule, and also, we will investigate the inhibitory effect of HDN636 on Hsp90 functions and illustrate the related molecule mechanisms, on the molecular, cellular and animal levels, and finally discover the molecular mechanisms underlying the anticancer activity of HDN636. This work will discover a novel Hsp90 inhibitor HDN636, and thus provide a promising lead compound for the development of such kind of Hsp90 inhibitors. Moreover, the discovery and identification of novel binding sites and their functions will be very helpful for the design and modification of novel Hsp90 inhibitors. Finally, this project will be quite important in the application of marine microbial resources and the development of marine innovative drugs.