Hsp90 Inhibitors

描述（由申请人提供）：Hsp90是一种分子伴侣，负责将新生多肽折叠成具有生物活性的天然结构。许多依赖于Hsp90进行构象成熟的蛋白质与恶性生长和增殖直接相关。抑制Hsp90导致Hsp90-客户蛋白复合物的不稳定，导致蛋白底物的泛素化和蛋白酶体降解。因此，Hsp90的抑制剂代表了一种有希望的治疗癌症的新方法，因为多个化疗靶点可以同时靶向。两种具有抗Hsp90活性的天然产物与Hsp90共结晶，并对其结构进行了解析。基于这些共晶结构，设计了新的Hsp90抑制剂，停靠在n端ATP结合位点，并合成了初始化合物。对这些化合物的初步测试已经鉴定出几种具有特殊活性的分子。此外，c端核苷酸结合位点的新抑制剂已被制备和评价。一种c端抑制剂的活性比新生物素高100 ~ 700倍。本提案的目的是制备新的Hsp90抑制剂，与已知的天然产物抑制剂相比，具有更高的亲和力和溶解度。这些分子将通过偶联实验（n端ATP结合位点）、细胞Hsp90客户蛋白降解实验和细胞毒性研究来评估其对Hsp90的生物活性。在与其他研究人员的合作下，这些分子与Hsp90结合的共晶结构将被解决，这些分子的体内研究将在前列腺癌和乳腺癌的小鼠异种移植模型中进行。

DESCRIPTION (provided by applicant): Hsp90 is a molecular chaperone responsible for folding nascent polypeptides into biologically active native structures. Many of the proteins dependent upon Hsp90 for conformational maturation are directly associated with malignant growth and proliferation. Inhibition of Hsp90 results in the destabilization of Hsp90-client protein complexes, resulting in ubiquitination and proteasomal degradation of the protein substrate. Consequently, inhibitors of Hsp90 represent a promising new approach toward the treatment of cancer because multiple chemotherapeutic targets can be simultaneously targeted. Two natural products with potent activity against Hsp90 have been co-crystallized with Hsp90 and the structures solved. Based on these co-crystal structures, new inhibitors of Hsp90 have been designed, docked to the N-terminal ATP binding site, and initial compounds synthesized. Preliminary testing of these compounds has resulted in the identification of several molecules with exceptional activity. In addition, new inhibitors of the C-terminal nucleotide binding site have been prepared and evaluated. One C-terminal inhibitor was shown to be >700 x more active than novobiocin. The objectives of this proposal are to prepare new Hsp90 inhibitors with increased affinity and solubility, as compared to the known natural product inhibitors. These molecules will be evaluated for their biological activity against Hsp90 by a coupled assay (N-terminal ATP binding site), a cellular Hsp90 client protein degradation assay, and by cytotoxicity studies. In collaboration with other researchers, the co-crystal structure of these molecules bound to Hsp90 will be solved and in vivo studies of these molecules will be performed in murine xenograft models of prostate and breast cancer.