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
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.
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