New molecular target and its inhibitors for use against pancreatic cancer

描述(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，由于胰腺癌疾病的复杂性，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(Hsp90)通过同时下调许多癌基因在治疗这种疾病中具有显著的优势。几种Hsp90抑制剂在临床前和I/II期临床试验中显示出对各种实体肿瘤和白血病的抗癌活性。这些经典的Hsp90抑制剂阻断ATP结合以抑制Hsp90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Hsp90抑制剂都没有完成FDA批准的第三阶段试验。这些经典的Hsp90抑制剂通过阻断三磷酸腺苷与Hsp90的结合而产生的临床益处还需要进一步验证。由于Hsp90的伴侣活性依赖于与辅伴侣形成多个蛋白质超伴侣复合体，因此在不同的伴侣阶段破坏Hsp90-辅伴侣的相互作用将实现对Hsp90的抑制。特别是，CDC37(在癌症中上调)在加载Hsp90超级伴侣复合体中的激酶客户蛋白方面发挥着核心作用。我们的长期目标是评估破坏Hsp90-CDc37相互作用作为抑制Hsp90的新机制，并寻找新的抑制剂来破坏Hsp90-CDc37用于胰腺癌治疗。我们假设，中断Hsp90-CDC37相互作用，而不影响ATP与Hsp90的结合，将阻止客户蛋白加载到超级伴侣复合体，并诱导客户蛋白过早降解。这些破坏Hsp90-CDC37相互作用的新型抑制剂将对胰腺癌细胞中的Hsp90活性显示出更特异的抑制作用。目的1：寻找破坏Hsp90-CDC37相互作用的新结构支架。目的2：评价Hsp90-CDC37相互作用，确定通过破坏蛋白质-蛋白质相互作用而体外抑制Hsp90的化合物。目的3：研究Aim 2中筛选的化合物在体内对胰腺癌的抗癌作用。 公共卫生相关性：这项研究计划将通过破坏Hsp90-CDC37复合体来评估新的靶点，并确定一种新的Hsp90抑制剂用于治疗胰腺癌。该抑制剂不会阻断Hsp90的ATP结合位点。因此，该抑制物对Hsp90的抑制具有更高的特异性，对胰腺癌有较好的疗效。

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.