title: Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group.
abstract: In contrast to studies on class I histone deacetylase (HDAC) inhibitors, the elucidation of the molecular mechanisms and therapeutic potential of class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) is impaired by the lack of potent and selective chemical probes. Here we report the discovery of inhibitors that fill this void with an unprecedented metal-binding group, trifluoromethyloxadiazole (TFMO), which circumvents the selectivity and pharmacologic liabilities of hydroxamates. We confirm direct metal binding of the TFMO through crystallographic approaches and use chemoproteomics to demonstrate the superior selectivity of the TFMO series relative to a hydroxamate-substituted analog. We further apply these tool compounds to reveal gene regulation dependent on the catalytic active site of class IIa HDACs. The discovery of these inhibitors challenges the design process for targeting metalloenzymes through a chelating metal-binding group and suggests therapeutic potential for class IIa HDAC enzyme blockers distinct in mechanism and application compared to current HDAC inhibitors.
authors.affiliation: Tempero Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Lobera
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Madauss
authors.forename: Denise T
authors.initials: DT
authors.lastname: Pohlhaus
authors.forename: Quentin G
authors.initials: QG
authors.lastname: Wright
authors.forename: Mark
authors.initials: M
authors.lastname: Trocha
authors.forename: Darby R
authors.initials: DR
authors.lastname: Schmidt
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Trump
authors.forename: Martha S
authors.initials: MS
authors.lastname: Head
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Hofmann
authors.forename: Monique
authors.initials: M
authors.lastname: Murray-Thompson
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schwartz
authors.forename: Subhas
authors.initials: S
authors.lastname: Chakravorty
authors.forename: Zining
authors.initials: Z
authors.lastname: Wu
authors.forename: Palwinder K
authors.initials: PK
authors.lastname: Mander
authors.forename: Laurens
authors.initials: L
authors.lastname: Kruidenier
authors.forename: Robert A
authors.initials: RA
authors.lastname: Reid
authors.forename: William
authors.initials: W
authors.lastname: Burkhart
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Turunen
authors.forename: James X
authors.initials: JX
authors.lastname: Rong
authors.forename: Craig
authors.initials: C
authors.lastname: Wagner
authors.forename: Mary B
authors.initials: MB
authors.lastname: Moyer
authors.forename: Carrow
authors.initials: C
authors.lastname: Wells
authors.forename: Xuan
authors.initials: X
authors.lastname: Hong
authors.forename: John T
authors.initials: JT
authors.lastname: Moore
authors.forename: Jon D
authors.initials: JD
authors.lastname: Williams
authors.forename: Dulce
authors.initials: D
authors.lastname: Soler
authors.forename: Shomir
authors.initials: S
authors.lastname: Ghosh
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nolan
mesh_terms: D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010069:Oxadiazoles / Q000737:chemistry; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D009942:Organometallic Compounds; D010069:Oxadiazoles; D006655:Histone Deacetylases; D015032:Zinc