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Discovery and validation of small-molecule heat-shock protein 90 inhibitors through multimodality molecular imaging in living subjects

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Discovery and validation of small-molecule heat-shock protein 90 inhibitors through multimodality molecular imaging in living subjects

dc.contributor.author	Chan, Carmel T.	es_ES
dc.contributor.author	Reeves, Robert E.	es_ES
dc.contributor.author	Geller, Ron	es_ES
dc.contributor.author	Yaghoubi, Shahriar S.	es_ES
dc.contributor.author	Hoehne, Aileen	es_ES
dc.contributor.author	Solow-Cordero, David E.	es_ES
dc.contributor.author	Chiosis, Gabriela	es_ES
dc.contributor.author	Massoud, Tarik F.	es_ES
dc.contributor.author	Paulmurugan, Ramasamy	es_ES
dc.contributor.author	Gambhir, Sanjiv S.	es_ES
dc.date.accessioned	2015-06-19T10:21:23Z
dc.date.available	2015-06-19T10:21:23Z
dc.date.issued	2012	es_ES
dc.identifier.citation	Proceedings of the National Academy of Sciences of the United States of America Vol. 109 Issue 37: pp. E2476-E2485	es_ES
dc.identifier.uri	http://hdl.handle.net/10550/44581
dc.description.abstract	Up-regulation of the folding machinery of the heat-shock protein 90 (Hsp90) chaperone protein is crucial for cancer progression. The two Hsp90 isoforms (α and β) play different roles in response to chemotherapy. To identify isoform-selective inhibitors of Hsp90(α/β)/cochaperone p23 interactions, we developed a dual-luciferase (Renilla and Firefly) reporter system for high-throughput screening (HTS) and monitoring the efficacy of Hsp90 inhibitors in cell culture and live mice. HTS of a 30,176 small-molecule chemical library in cell culture identified a compound, N-(5-methylisoxazol-3-yl)-2-[4-(thiophen-2-yl)-6-(trifluoromethyl)pyrimidin-2-ylthio]acetamide (CP9), that binds to Hsp90(α/β) and displays characteristics of Hsp90 inhibitors, i.e., degradation of Hsp90 client proteins and inhibition of cell proliferation, glucose metabolism, and thymidine kinase activity, in multiple cancer cell lines. The efficacy of CP9 in disrupting Hsp90(α/β)/p23 interactions and cell proliferation in tumor xenografts was evaluated by non-invasive, repetitive Renilla luciferase and Firefly luciferase imaging, respectively. At 38 h posttreatment (80 mg/kg × 3, i.p.), CP9 led to selective disruption of Hsp90α/p23 as compared with Hsp90β/p23 interactions. Small-animal PET/CT in the same cohort of mice showed that CP9 treatment (43 h) led to a 40% decrease in 18F-fluorodeoxyglucose uptake in tumors relative to carrier control-treated mice. However, CP9 did not lead to significant degradation of Hsp90 client proteins in tumors. We performed a structural activity relationship study with 62 analogs of CP9 and identified A17 as the lead compound that outperformed CP9 in inhibiting Hsp90(α/β)/p23 interactions in cell culture. Our efforts demonstrated the power of coupling of HTS with multimodality molecular imaging and led to identification of Hsp90 inhibitors.	es_ES
dc.subject	drug development	es_ES
dc.subject	small-molecule inhibitors	es_ES
dc.subject	co-chaperone p23	es_ES
dc.subject	bioluminescence imaging	es_ES
dc.subject	PET/computed tomography imaging	es_ES
dc.title	Discovery and validation of small-molecule heat-shock protein 90 inhibitors through multimodality molecular imaging in living subjects	es_ES
dc.type	journal article	es_ES
dc.identifier.doi	10.1073/pnas.1205459109	es_ES
dc.identifier.idgrec	090536	es_ES