title: Syntheses and discovery of a novel class of cinnamic hydroxamates as histone deacetylase inhibitors by multimodality molecular imaging in living subjects.
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 used a dual-luciferase reporter system in cell culture and living mice by bioluminescence imaging (BLI). On the basis of 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)/p23 interactions 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, p21(waf1) upregulation, and acetylated histone H3 levels. 1A12 was efficacious in tumor xenografts expressing Hsp90(α)/p23 reporters relative to carrier control-treated mice as determined by BLI. Small animal (18)F-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 approximately 3.5-fold. Taken together, our results describe the discovery and initial preclinical validation of a novel selective HDAC inhibitor.
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California. Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, California. Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: C T
authors.initials: CT
authors.lastname: Chan
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: J
authors.initials: J
authors.lastname: Qi
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: W
authors.initials: W
authors.lastname: Smith
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: R
authors.initials: R
authors.lastname: Paranol
authors.affiliation: Harvard Medical School, Boston, Massachusetts. Massachusetts General Hospital, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts.
authors.forename: R
authors.initials: R
authors.lastname: Mazitschek
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: N
authors.initials: N
authors.lastname: West
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California. Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, California. Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: R
authors.initials: R
authors.lastname: Reeves
authors.affiliation: Department of Medicine and Program in Molecular Pharmacology and Medical Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: G
authors.initials: G
authors.lastname: Chiosis
authors.affiliation: Broad Institute, Cambridge, Massachusetts.
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts.
authors.forename: J E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California. Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, California. Bio-X Program, Stanford University School of Medicine, Stanford, California.
authors.forename: R
authors.initials: R
authors.lastname: Paulmurugan
authors.affiliation: Department of Radiology, Stanford University School of Medicine, Stanford, California. Molecular Imaging Program at Stanford (MIPS), Stanford University School of Medicine, Stanford, California. Bio-X Program, Stanford University School of Medicine, Stanford, California. Department of Bioengineering, Stanford University School of Medicine, Stanford, California. Division of Nuclear Medicine, Stanford University School of Medicine, Stanford, California. sgambhir@stanford.edu.
authors.forename: S S
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000107:Acetylation; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D019788:Fluorodeoxyglucose F18; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000302:isolation & purification* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000302:isolation & purification*; D051379:Mice; D057054:Molecular Imaging; D064847:Multimodal Imaging; D022423:Myeloid Cells / Q000187:drug effects
chemical_list: D002934:Cinnamates; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019788:Fluorodeoxyglucose F18; C029010:cinnamic acid; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases