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Research Article

Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase (HDAC) Inhibitors by Multimodality Molecular Imaging in Living Subjects

Carmel T Chan, Jun Qi, William Smith, Ronald Paranal, Ralph Mazitschek, Nathan West, Robert Reeves, Gabriela Chiosis, Stuart L. Schreiber, James E Bradner, Ramasamy Paulmurugan and Sanjiv S Gambhir
Carmel T Chan
Radiology, Stanford Universtiy School of Medicine
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Jun Qi
Medical Oncology, Dana-Farber Cancer Institute
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William Smith
Medical Oncology, Dana-Farber Cancer Institute
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Ronald Paranal
Medical Oncology, Dana-Farber Cancer Institute
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Ralph Mazitschek
Center for Systems Biology, Massachusetts General Hospital
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Nathan West
Medical Oncology, Dana-Farber Cancer Institute
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Robert Reeves
DEPARTMENT OF RADIOLOGY, Stanford University
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Gabriela Chiosis
n/a, Memorial Sloan-Kettering Cancer Center
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Stuart L. Schreiber
Chemical Biology Program, The Broad Institute of MIT and Harvard
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James E Bradner
Department of Medical Oncology, Dana-Farber Cancer Institute
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Ramasamy Paulmurugan
Radiology, Stanford university School of Medicine
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Sanjiv S Gambhir
Radiology, Stanford University
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  • For correspondence: sgambhir@stanford.edu
DOI: 10.1158/0008-5472.CAN-14-0197
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Abstract

Histone deacetylases (HDAC) that regulate gene expression are being explored as cancer therapeutic targets. In this study, we focused on HDAC6 based on its ability to inhibit cancerous Hsp90 chaperone activities by disrupting Hsp90/p23 interactions. To identify novel HDAC6 inhibitors, we employed a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). Based on existing knowledge, a library of hydrazone compounds was generated for screening by coupling cinnamic hydroxamates with aldehydes and ketones. Potency and selectivity were determined by in vitro HDAC profiling assays with further evaluation to inhibit Hsp90(α/β)/p23interactions by BLI. In this manner, we identified compound 1A12 as a dose-dependent inhibitor of Hsp90(α/β)/p23 interactions, UKE-1 myeloid cell proliferation, p21waf1 upregulation and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(α/β)/p23 reporters relative to carrier control treated mice as determined by BLI. Small animal 18F-FDG PET/CT imaging on the same cohort showed that 1A12 also inhibited glucose metabolism relative to control subjects. Ex vivo analyses of tumor lysates showed that 1A12 administration upregulated acetylated-H3 by ~3.5-fold. Taken together our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor.

  • Received January 27, 2014.
  • Revision received September 4, 2014.
  • Accepted September 24, 2014.
  • Copyright © 2014, American Association for Cancer Research.
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Published OnlineFirst October 15, 2014
doi: 10.1158/0008-5472.CAN-14-0197

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Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase (HDAC) Inhibitors by Multimodality Molecular Imaging in Living Subjects
Carmel T Chan, Jun Qi, William Smith, Ronald Paranal, Ralph Mazitschek, Nathan West, Robert Reeves, Gabriela Chiosis, Stuart L. Schreiber, James E Bradner, Ramasamy Paulmurugan and Sanjiv S Gambhir
Cancer Res October 15 2014 DOI: 10.1158/0008-5472.CAN-14-0197

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Syntheses and Discovery of a Novel Class of Cinnamic Hydroxamates as Histone Deacetylase (HDAC) Inhibitors by Multimodality Molecular Imaging in Living Subjects
Carmel T Chan, Jun Qi, William Smith, Ronald Paranal, Ralph Mazitschek, Nathan West, Robert Reeves, Gabriela Chiosis, Stuart L. Schreiber, James E Bradner, Ramasamy Paulmurugan and Sanjiv S Gambhir
Cancer Res October 15 2014 DOI: 10.1158/0008-5472.CAN-14-0197
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