Design and development of histone deacetylase (HDAC) chemical probes for cell-based profiling.

Abstract:

:Histone deacetylases (HDACs) contribute to regulation of gene expression by mediating higher-order chromatin structures. They assemble into large multiprotein complexes that regulate activity and specificity. We report the development of small molecule probes with class IIa and pan-HDAC activity that contain photoreactive crosslinking groups and either a biotin reporter, or a terminal alkyne handle for subsequent bioorthogonal ligation. The probes retained inhibitory activity against recombinant HDAC proteins and caused an accumulation of acetylated histone and tubulin following cell treatment. The versatility of the probes has been demonstrated by their ability to photoaffinity modify HDAC targets in vitro. An affinity enrichment probe was used in conjunction with mass spectrometry proteomics to isolate HDACs and their interacting proteins in a native proteome. The performance of the probes in recombinant versus cell-based systems highlights issues for the development of chemoproteomic technologies targeting class IIa HDACs in particular.

journal_name

Mol Biosyst

journal_title

Molecular bioSystems

authors

Albrow VE,Grimley RL,Clulow J,Rose CR,Sun J,Warmus JS,Tate EW,Jones LH,Storer RI

doi

10.1039/c6mb00109b

subject

Has Abstract

pub_date

2016-05-24 00:00:00

pages

1781-9

issue

6

eissn

1742-206X

issn

1742-2051

journal_volume

12

pub_type

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