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Quantitative measurement of intracellular HDAC1/2 drug occupancy using a trans-cyclooctene largazole thiol probe.

ABSTRACT: Histone deacetylases (HDACs) regulate diverse cellular processes, and are promising targets for a number of diseases. Here we describe the design and utilization of a largazole-based chemical probe to quantitatively measure the intracellular occupancy of HDAC1 and HDAC2 by dacinostat. Surprisingly, the probe was unable to enrich HDAC3 despite its nanomolar potency in a biochemical assay, further proving the necessity of cell-based target occupancy assays to understand compound potency in physiologically-relevant settings. This occupancy assay has the potential to aid the development of novel HDAC1/2 inhibitors in drug discovery.

SUBMITTER: Xu H

PROVIDER: S-EPMC6072125 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Quantitative measurement of intracellular HDAC1/2 drug occupancy using a trans-cyclooctene largazole thiol probe.

Xu Hua H Roberts Lee R LR Chou Song S Pierce Betsy B Narayanan Arjun A Jones Lyn H LH

MedChemComm 20170109 4

Histone deacetylases (HDACs) regulate diverse cellular processes, and are promising targets for a number of diseases. Here we describe the design and utilization of a largazole-based chemical probe to quantitatively measure the intracellular occupancy of HDAC1 and HDAC2 by dacinostat. Surprisingly, the probe was unable to enrich HDAC3 despite its nanomolar potency in a biochemical assay, further proving the necessity of cell-based target occupancy assays to understand compound potency in physiol ...[more]

PMID: 30108795

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