FP Assay for Isolation of Hsp90 Inhibitors (RMI)

用于分离 Hsp90 抑制剂 (RMI) 的 FP 测定

• 批准号: 7060110
• 负责人: GABRIELA CHIOSIS
• 金额: $ 0.52万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060110
• 关键词: antibiotics; antineoplastics; bioassay; biotechnology; chemical registry /resource; combinatorial chemistry; diagnosis design /evaluation; drug discovery /isolation; fluorescence polarization; heat shock proteins; inhibitor /antagonist; molecular chaperones; neoplasm /cancer chemotherapy; neuropharmacologic agent; peptide library; proteomics

DESCRIPTION (provided by applicant): The long-term goal of this initiative is to identify novel Hsp90 inhibitors with use in cancer therapy and in the treatment of neurodegenerative diseases. The goal of the current effort is to translate our Hsp90 fluorescence polarization assay to MLSCN centers. This assay probes the competitive binding of red-shifted cy3B-labeled geldanamycin to Hsp90 from cell lysates. Funding for the development of the assay has been provided in part by R03 NS050838-01; Chiosis, G (PI). Hsp90 is a chaperone with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Recent evidence suggests additional applications of Hsp90 inhibitors in neurodegenerative diseases, nerve injuries, inflammation and infection. Several natural products that inactivate Hsp90 function have anti-tumor effects in in vitro and in vivo models of cancer. However, due to the role of Hsp90 in normal cellular homeostasis, it remained unclear whether Hsp90 inhibitors will be sufficiently specific for use as therapeutic agents. Early clinical results with 17AAG, the first Hsp90 inhibitor to enter clinical trials, suggest that these fears may be unfounded. These studies confirm that Hsp90 is a promising target for novel cancer therapeutics and pave the road for the introduction of Hsp90 inhibitors in the clinic. The potential of Hsp90 inhibitors as therapeutics in other diseases has been less explored due to limitations with the current inhibitors (i.e. 17AAG is not crossing the blood-brain barrier, BBB). Currently there is thus, increasing interest in developing novel inhibitors of this protein. We have conducted pioneering research in the area and designed the first synthetic class of Hsp90 inhibitors, the purine-scaffold class (PU-class). We have also designed and developed several assays that probe biochemical and cellular inhibition of Hsp90. One such assay is proposed here for use in MLSCN. Discovery of novel Hsp90 inhibitors based on diverse chemical skeletons is necessary to fully harvest the therapeutic potential of the chaperone, and we propose here that such diversity may be obtained by screening large libraries of compounds against this target.

描述（由申请人提供）：该计划的长期目标是鉴定用于癌症治疗和神经退行性疾病治疗的新型 Hsp90 抑制剂。当前努力的目标是将我们的 Hsp90 荧光偏振测定转化为 MLSCN 中心。该测定探测红移的 cy3B 标记的格尔德霉素与细胞裂解物中的 Hsp90 的竞争性结合。 R03 NS050838-01 提供了该测定法开发的部分资金；奇奥西斯，G (PI)。 Hsp90 是一种伴侣蛋白，在维持转化以及提高癌细胞的存活和生长潜力方面发挥着重要作用。最近的证据表明 Hsp90 抑制剂在神经退行性疾病、神经损伤、炎症和感染中的其他应用。几种使 Hsp90 功能失活的天然产物在体外和体内癌症模型中具有抗肿瘤作用。然而，由于 Hsp90 在正常细胞稳态中的作用，目前尚不清楚 Hsp90 抑制剂是否具有足够的特异性用作治疗剂。 17AAG（第一个进入临床试验的 Hsp90 抑制剂）的早期临床结果表明，这些担忧可能没有根据。这些研究证实，Hsp90 是新型癌症治疗的一个有前景的靶点，并为 Hsp90 抑制剂引入临床铺平了道路。由于当前抑制剂的局限性（即 17AAG 不能穿过血脑屏障，BBB），Hsp90 抑制剂作为其他疾病治疗方法的潜力较少被探索。因此，目前人们对开发这种蛋白质的新型抑制剂越来越感兴趣。我们在该领域进行了开创性研究，并设计了第一个合成类 Hsp90 抑制剂，即嘌呤支架类（PU 类）。我们还设计和开发了多种检测 Hsp90 生化和细胞抑制的检测方法。这里提出了一种用于 MLSCN 的此类测定。发现基于不同化学骨架的新型 Hsp90 抑制剂对于充分发挥伴侣的治疗潜力是必要的，我们在此提出，可以通过针对该靶点筛选大型化合物库来获得这种多样性。