Development of Hsp90 inhibitors for the treatment of cancer

描述(申请人提供)：到目前为止，对于转移性去势抵抗前列腺癌患者的治疗方法非常有限。由于前列腺癌的异质性，在前列腺癌中还没有一个特定的癌基因、突变、信号通路或危险因素被描述。前列腺癌的发生和发展有多种途径被描述。HSP90已被证明在前列腺癌中过度表达，并作为促进恶性生长和增殖的多个信号通路的枢纽，使其成为开发抑制剂的极佳靶点。与N端抑制物诱导有利于生存的热休克反应不同，C端抑制物不能，因此为癌症研究提供了一个新的范式。具体地说，我们的目标是制备新的Hsp90 C末端抑制剂的构象偏向类似物，通过一系列新的体外测试对其进行评估，然后将选定的化合物应用于前列腺癌的原位模型以确定其有效性。在这个项目完成后，我们的目标是生产出可在前列腺癌临床试验中进一步评估的化合物。

DESCRIPTION (provided by applicant): To date, there are very limited therapies for patients with metastatic castrate resistant prostate cancer. Due to the heterogeneity of prostate cancer no one specific oncogene, mutation, signaling pathways, or risk factor has been described in prostate cancer. Multiple pathways have been described to contribute to both the development as well as progression of prostate cancer. Hsp90 has been shown to be over-expressed in prostate cancer and serves as a hub for multiple signaling pathways that contribute to malignant growth and proliferation, making it an excellent target for the development of inhibitors. In contrast to N-terminal inhibitors that induce the pro-survival heat shock response, C-terminal inhibitors do not, and therefore provide a new paradigm in cancer research. Specifically, we aim to prepare conformationally biased analogues of new Hsp90 C-terminal inhibitors, evaluate them through a series of novel assays in vitro, and then administer select compounds to an orthotopic model of prostate cancer to determine their efficacy. Upon completion of this project, we aim to produce compounds amenable to further evaluation in clinical trials for prostate cancer.