Development of Hsp90 inhibitors for the treatment of cancer

描述（由申请人提供）：迄今为止，转移性去势抵抗性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，没有一个特定的致癌基因，突变，信号通路，或风险因素已被描述在前列腺癌。已经描述了多种途径有助于前列腺癌的发展和进展。Hsp 90已被证明在前列腺癌中过表达，并作为多种信号传导途径的枢纽，有助于恶性生长和增殖，使其成为开发抑制剂的极好靶点。与诱导促存活热休克反应的N-末端抑制剂相比，C-末端抑制剂不诱导促存活热休克反应，因此在癌症研究中提供了新的范例。具体而言，我们的目标是制备构象偏向的新的热休克蛋白90 C-末端抑制剂的类似物，通过一系列新的体外试验来评估它们，然后将选择的化合物施用到前列腺癌的原位模型中以确定它们的功效。在这个项目完成后，我们的目标是生产适合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.