Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors

Keris KrennHrubec, Brett L. Marshall, Mark Hedglin, Eric Verdin, Scott M. Ulrich

Research output: Contribution to journalArticle

134 Citations (Scopus)

Abstract

In this report, we describe new HDAC inhibitors designed to exploit a unique sub-pocket in the HDAC8 active site. These compounds were based on inspection of the available HDAC8 crystal structures bound to various inhibitors, which collectively show that the HDAC8 active site is unusually malleable and can accommodate inhibitor structures that are distinct from the canonical 'zinc binding group-linker-cap group' structures of SAHA, TSA, and similar HDAC inhibitors. Some inhibitors based on this new scaffold are >100-fold selective for HDAC8 over other class I and class II HDACs with IC50 values <1 μM against HDAC8. Furthermore, treatment of human cells with the inhibitors described here shows a unique pattern of hyperacetylated proteins compared with the broad-spectrum HDAC inhibitor TSA.

Original languageEnglish (US)
Pages (from-to)2874-2878
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume17
Issue number10
DOIs
StatePublished - May 15 2007

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Hydroxamic Acids
Histone Deacetylase Inhibitors
Catalytic Domain
Scaffolds
Inhibitory Concentration 50
Zinc
Crystal structure
Inspection
Cells
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

KrennHrubec, Keris ; Marshall, Brett L. ; Hedglin, Mark ; Verdin, Eric ; Ulrich, Scott M. / Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors. In: Bioorganic and Medicinal Chemistry Letters. 2007 ; Vol. 17, No. 10. pp. 2874-2878.
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Design and evaluation of 'Linkerless' hydroxamic acids as selective HDAC8 inhibitors. / KrennHrubec, Keris; Marshall, Brett L.; Hedglin, Mark; Verdin, Eric; Ulrich, Scott M.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 17, No. 10, 15.05.2007, p. 2874-2878.

Research output: Contribution to journalArticle

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