New molecular target and its inhibitors for use against pancreatic cancer

用于治疗胰腺癌的新分子靶点及其抑制剂

• 批准号: 7991829
• 负责人: DUXIN SUN
• 金额: $ 12.58万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7991829
• 关键词: Affect; Binding; Binding Sites; Biochemical Genetics; Cancer cell line; Cell Line; Client; Clinical; Clinical Trials; Complex; Disease; Drug Delivery Systems; Exhibits; Figs - dietary; Goals; HSP 90 inhibition; Health; Heat-Shock Proteins 90; In Vitro; Individual; Malignant Neoplasms; Malignant neoplasm of pancreas; Molecular Abnormality; Molecular Chaperones; Molecular Target; Oncogenes; Phase; Phase III Clinical Trials; Phosphotransferases; Play; Proteins; Research; Role; Solid; Specificity; Staging; Structure; anticancer activity; cancer cell; cancer therapy; in vivo; inhibitor/antagonist; leukemia; novel; pancreatic cancer cells; pre-clinical; premature; programs; protein degradation; protein protein interaction; scaffold

DESCRIPTION (provided by applicant): Pancreatic cancer is a complex disease with various biochemical and genetic abnormalities. Therefore, pursuing individual oncogene as a drug target is unlikely to be effective for pancreatic cancer due to the disease complexity. In this regard, inhibition of heat shock protein 90 (Hsp90) offers significant advantages in treatment of this disease by simultaneously downregulating many oncogenes. Several Hsp90 inhibitors exhibit anticancer activity against various solid cancers and leukemia in preclinical and phase I/II clinical trials. These classical Hsp90 inhibitors block ATP binding to inhibit Hsp90 chaperone activity, inducing premature release and proteasomal degradation of the client proteins in cancer cells. However, none of these classical Hsp90 inhibitors have completed phase III trials for FDA approval. The clinical benefits of these classical Hsp90 inhibitors by blocking ATP binding to Hsp90 need to be further validated. Since the Hsp90 chaperoning activity depends on the formation of multiple protein superchaperone complexes with cochaperones, disruption of the Hsp90-cochaperone interaction at various chaperoning stages will achieve Hsp90 inhibition. In particular, Cdc37 (up-regulated in cancers) plays a central role in loading kinase client proteins in the Hsp90 superchaperone complexes. Our long term goal is to evaluate disruption of Hsp90-Cdc37 interaction as a novel mechanism to inhibit Hsp90 and identify novel inhibitors to disrupt Hsp90-Cdc37 for use of pancreatic cancer therapy. We hypothesize that disruption of Hsp90-Cdc37 interaction, without affecting ATP binding to Hsp90, will block client protein loading to the superchaperone complex and induce premature client protein degradation. These novel inhibitors that disrupt Hsp90-Cdc37 interaction will exhibit more specific inhibition of Hsp90 activity in pancreatic cancer cells. Aim 1: To identify new structure scaffolds to disrupt Hsp90-Cdc37 interaction Aim 2: To evaluate Hsp90-Cdc37 interaction and confirm the selected compounds to inhibit Hsp90 by disrupting protein-protein interaction in vitro cell lines Aim 3: To study the anticancer efficacy of the selected compounds from aim 2 in pancreatic cancers in vivo PUBLIC HEALTH RELEVANCE: This research program will evaluate novel targets by disrupting Hsp90-Cdc37 complex and identify a novel Hsp90 inhibitor in use against pancreatic cancers. The inhibitor will not block the ATP binding sites of Hsp90. Therefore, the inhibitor may offer more specificity for Hsp90 inhibition and provide preferential efficacy against pancreatic cancers.

描述（由申请人提供）：胰腺癌是一种具有多种生化和遗传异常的复杂疾病。因此，由于疾病的复杂性，追求单个癌基因作为药物靶点不太可能对胰腺癌有效。在这方面，抑制热休克蛋白90（Hsp 90）通过同时下调许多癌基因在治疗这种疾病中提供了显著的优势。几种Hsp 90抑制剂在临床前和I/II期临床试验中显示出对各种实体癌和白血病的抗癌活性。这些经典的Hsp 90抑制剂阻断ATP结合以抑制Hsp 90分子伴侣活性，诱导癌细胞中客户蛋白的过早释放和蛋白酶体降解。然而，这些经典的Hsp 90抑制剂都没有完成FDA批准的III期试验。这些经典的Hsp 90抑制剂通过阻断ATP与Hsp 90结合而产生的临床益处需要进一步验证。由于Hsp 90分子伴侣活性依赖于与辅分子伴侣形成多个蛋白质超分子伴侣复合物，因此在各个分子伴侣阶段破坏Hsp 90-辅分子伴侣相互作用将实现Hsp 90抑制。特别是，Cdc 37（在癌症中上调）在装载Hsp 90超伴侣复合物中的激酶客户蛋白中起着核心作用。我们的长期目标是评估Hsp 90-Cdc 37相互作用的破坏作为抑制Hsp 90的新机制，并鉴定用于胰腺癌治疗的破坏Hsp 90-Cdc 37的新抑制剂。我们假设，在不影响ATP与Hsp 90结合的情况下，Hsp 90-Cdc 37相互作用的破坏将阻止客户蛋白加载到超级伴侣复合物并诱导过早的客户蛋白降解。这些破坏Hsp 90-Cdc 37相互作用的新型抑制剂将在胰腺癌细胞中表现出更特异性的Hsp 90活性抑制。目标1：目的2：通过体外细胞系研究Hsp 90-Cdc 37相互作用，验证所选化合物对Hsp 90的抑制作用。目的3：研究所选化合物对胰腺癌的体内抗肿瘤作用 公共卫生相关性：这项研究计划将通过破坏Hsp 90-Cdc 37复合物来评估新的靶点，并确定一种用于治疗胰腺癌的新型Hsp 90抑制剂。该抑制剂不会阻断Hsp 90的ATP结合位点。因此，该抑制剂可提供对Hsp 90抑制的更高特异性，并提供针对胰腺癌的优先功效。