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）：胰腺癌是一种复杂的疾病，具有各种生化和遗传异常。因此，由于疾病的复杂性，追求个体癌基作为药物靶标的对胰腺癌不太可能有效。在这方面，热休克蛋白90（HSP90）的抑制通过同时下调许多癌基因，在治疗该疾病方面具有显着优势。在临床前和I/II期临床试验中，几种HSP90抑制剂表现出针对各种固体癌和白血病的抗癌活性。这些经典的HSP90抑制剂阻断了ATP与抑制HSP90伴侣活性的结合，从而诱导了癌细胞中客户蛋白的过早释放和蛋白酶体降解。但是，这些经典的HSP90抑制剂均未完成III期试验以进行FDA批准。这些经典HSP90抑制剂的临床益处需要进一步验证ATP与HSP90的结合。由于HSP90伴侣的活性取决于与联蛋白的多种蛋白质超副酮配合物的形成，因此在各个伴侣阶段，HSP90-辅助酮相互作用的破坏将实现HSP90的抑制作用。特别是，cdc37（癌症中的上调）在将激酶客户蛋白加载在HSP90超副酮配合物中起着核心作用。我们的长期目标是评估HSP90-CDC37相互作用的破坏，作为一种抑制HSP90的新机制，并确定了新型抑制剂，以破坏HSP90-CDC37用于使用胰腺癌治疗。我们假设HSP90-CDC37相互作用的破坏而不会影响ATP与HSP90的结合，将阻止客户蛋白蛋白质的蛋白质加载到超副酮复合体中，并诱导过早的客户蛋白蛋白质降解。这些破坏HSP90-CDC37相互作用的新型抑制剂将表现出对胰腺癌细胞中HSP90活性的更特异性抑制作用。目的1：确定破坏HSP90-CDC37相互作用的新结构脚手架的目标2：评估HSP90-CDC37相互作用并确认所选化合物以抑制HSP90，通过在体外细胞系中破坏蛋白质 - 蛋白质相互作用的目标3：研究来自选定的化合物的抗抗癌物的抗抗菌作用。 公共卫生相关性：该研究计划将通过破坏HSP90-CDC37复合物并确定针对胰腺癌使用的新型HSP90抑制剂来评估新的目标。抑制剂不会阻止HSP90的ATP结合位点。因此，抑制剂可能对HSP90抑制作用提供更多特异性，并对胰腺癌提供优先效率。