title: Identification of HDAC6-Selective Inhibitors of Low Cancer Cell Cytotoxicity.
abstract: The histone deacetylases (HDACs) occur in 11 different isoforms, and these enzymes regulate the activity of a large number of proteins involved in cancer initiation and progression. The discovery of isoform-selective HDAC inhibitors (HDACIs) is desirable, as it is likely that such compounds would avoid some of the undesirable side effects found with the first-generation inhibitors. A series of HDACIs previously reported by us were found to display some selectivity for HDAC6 and to induce cell-cycle arrest and apoptosis in pancreatic cancer cells. In the present work, we show that structural modification of these isoxazole-based inhibitors leads to high potency and selectivity for HDAC6 over HDAC1-3 and HDAC10, while unexpectedly abolishing their ability to block cell growth. Three inhibitors with lower HDAC6 selectivity inhibit the growth of cell lines BxPC3 and L3.6pl, and they only induce apoptosis in L3.6pl cells. We conclude that HDAC6 inhibition alone is insufficient for disruption of cell growth, and that some degree of class 1 HDAC inhibition is required. Moreover, the highly selective HDAC6Is reported herein that are weakly cytotoxic may find use in cancer immune system reactivation.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA.|Psychogenics Inc., Tarrytown, NY, 10591, USA.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Gaisina
authors.affiliation: Psychogenics Inc., Tarrytown, NY, 10591, USA.
authors.forename: Werner
authors.initials: W
authors.lastname: Tueckmantel
authors.affiliation: Center for Developmental Therapeutics, Feinberg School of Medicine, Northwestern University, Evanston, IL, 60208, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ugolkov
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA.
authors.forename: Sida
authors.initials: S
authors.lastname: Shen
authors.affiliation: Center for Developmental Therapeutics, Feinberg School of Medicine, Northwestern University, Evanston, IL, 60208, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hoffen
authors.affiliation: Center for Developmental Therapeutics, Feinberg School of Medicine, Northwestern University, Evanston, IL, 60208, USA.|Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Evanston, IL, 60208, USA.
authors.forename: Oleksii
authors.initials: O
authors.lastname: Dubrovskyi
authors.affiliation: Center for Developmental Therapeutics, Feinberg School of Medicine, Northwestern University, Evanston, IL, 60208, USA.|Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Evanston, IL, 60208, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mazar
authors.affiliation: Department of Immunology and Division of Oncology Research, College of Medicine, Mayo Clinic, 13-42 Guggenheim, Rochester, MN, 55905, USA.
authors.forename: Renee A
authors.initials: RA
authors.lastname: Schoon
authors.affiliation: Department of Immunology and Division of Oncology Research, College of Medicine, Mayo Clinic, 13-42 Guggenheim, Rochester, MN, 55905, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Billadeau
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, 60612, USA. kozikowa@uic.edu.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC6 selectivity; histone deacetylases; hydroxamic acids; immune activation; inhibitors; pancreatic cancer