title: Identification of histone deacetylase inhibitors with benzoylhydrazide scaffold that selectively inhibit class I histone deacetylases.
abstract: Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clinical anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compounds are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compound, UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biological activities in suppressing tumor cell proliferation support further preclinical development of the UF010 class of compounds for potential therapeutic applications.
authors.affiliation: Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA; Department of Biochemistry and Molecular Biology, College of Life Sciences, Northwest Agriculture and Forestry University, Yangling, Shaanxi 712100, China.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Stowe
authors.affiliation: The Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Christie E
authors.initials: CE
authors.lastname: Pinello
authors.affiliation: Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Guimei
authors.initials: G
authors.lastname: Tian
authors.affiliation: The Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Madoux
authors.affiliation: Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA; Department of Urology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Zhao
authors.affiliation: Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA.
authors.forename: Jian-Liang
authors.initials: JL
authors.lastname: Li
authors.affiliation: Reaction Biology Corporation, 1 Great Valley Parkway Suite 2, Malvern, PA 19355, USA.
authors.forename: Yuren
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Reaction Biology Corporation, 1 Great Valley Parkway Suite 2, Malvern, PA 19355, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Reaction Biology Corporation, 1 Great Valley Parkway Suite 2, Malvern, PA 19355, USA.
authors.forename: Haiching
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Molecular Therapeutics, Scripps Florida, Jupiter, FL 33458, USA; The Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.affiliation: Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: dliao@ufl.edu.
authors.forename: Daiqing
authors.initials: D
authors.lastname: Liao
mesh_terms: D000107:Acetylation; D001549:Benzamides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D007700:Kinetics; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006834:Hydrazines; C000602704:UF010 compound; C029424:hydrazine; D006655:Histone Deacetylases