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Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
A Rational Approach for the Identification of Non-Hydroxamate HDAC6-Selective Inhibitors
Laura Goracci1,2, Nathalie Deschamps1, Giuseppe Marco Randazzo1
1School of Pharmaceutical Sciences, University of Geneva, University of Lausanne Quai Ernest-Ansermet, 30, CH-1211, Geneva 4, Switzerland.
Abstract:
The human histone deacetylase isoform 6 (HDAC6) has been demonstrated to play a major role in cell motility and aggresome formation, being interesting for the treatment of multiple tumour types and neurodegenerative conditions. Currently, most HDAC inhibitors in preclinical or clinical evaluations are non-selective inhibitors, characterised by a hydroxamate zinc-binding group (ZBG) showing off-target effects and mutagenicity. The identification of selective HDAC6 inhibitors with novel chemical properties has not been successful yet, also because of the absence of crystallographic information that makes the rational design of HDAC6 selective inhibitors difficult. Using HDAC inhibitory data retrieved from the ChEMBL database and ligand-based computational strategies, we identified 8 original new non-hydroxamate HDAC6 inhibitors from the SPECS database, with activity in the low μM range. The most potent and selective compound, bearing a hydrazide ZBG, was shown to increase tubulin acetylation in human cells. No effects on histone H4 acetylation were observed. To the best of our knowledge, this is the first report of an HDAC6 selective inhibitor bearing a hydrazide ZBG. Its capability to passively cross the blood-brain barrier (BBB), as observed through PAMPA assays, and its low cytotoxicity in vitro, suggested its potential for drug development.
Insights
Researchers identified novel, selective HDAC6 inhibitors without hydroxamate groups, crucial for treating cancers and neurodegenerative diseases. The most potent compound targets tubulin acetylation, showing potential for drug development with low cytotoxicity and blood-brain barrier penetration.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Neuroscience
Background:
- Human histone deacetylase isoform 6 (HDAC6) is implicated in cell motility and aggresome formation, relevant to cancer and neurodegenerative diseases.
- Existing HDAC inhibitors often lack selectivity, exhibiting off-target effects and mutagenicity due to hydroxamate zinc-binding groups.
- The absence of crystallographic data hinders the rational design of selective HDAC6 inhibitors.
Purpose of the Study:
- To identify novel, selective, non-hydroxamate HDAC6 inhibitors.
- To explore new chemical scaffolds for HDAC6 inhibition.
- To assess the potential of identified compounds for therapeutic applications.
Main Methods:
- Utilized HDAC inhibitory data from the ChEMBL database.
- Employed ligand-based computational strategies for inhibitor identification.
- Screened compounds from the SPECS database.
- Validated activity and selectivity through in vitro assays, including tubulin and histone acetylation.
- Assessed blood-brain barrier penetration using PAMPA assays and evaluated cytotoxicity.
Main Results:
- Identified 8 novel non-hydroxamate HDAC6 inhibitors with low μM activity.
- The most potent inhibitor features a hydrazide zinc-binding group.
- This compound selectively increased tubulin acetylation without affecting histone H4 acetylation in human cells.
- Demonstrated passive blood-brain barrier penetration and low in vitro cytotoxicity.
Conclusions:
- This study reports the first selective HDAC6 inhibitor with a hydrazide zinc-binding group.
- The identified compound shows promise for developing new therapeutics for cancer and neurodegenerative conditions.
- The novel chemical scaffold and favorable drug-like properties warrant further investigation for drug development.
