ArticleNature chemical biology2022
Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target.
Article in Nature chemical biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 75 papers, 1 of them a synthesis that pooled it.
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Who cites it
75 citing papers in PubMed, 1 synthesis or guideline pooled it, 108 citations in OpenAlex.
- Research trends of protein palmitoylation in cancer from 2004 to 2024: a bibliometric and visualization analysis.Frontiers in oncology · 2025Pooled it
- Hydroxamic Acids as HDAC Inhibitor Drug Leads for Malaria.Medicinal research reviews · 2026Review
- KDAC6 alters cell morphology and motility through positive and negative modulation of F-actin distribution.FEBS open bio · 2026Article
- An AI-Assisted Workflow for Rapid Prioritization of FDA-Approved Drugs as HDAC3 Inhibitor Candidates for Drug Repurposing.Biology · 2026Article
- Mechanism-based inhibition of zinc-dependent histone deacetylases.RSC chemical biology · 2026Review
- Optimizing pyrazine-2-carboxamide derivatives as dual FLT3/HDAC inhibitors with enhanced pharmacokinetics and immunotherapeutic potential.Acta pharmaceutica Sinica. B · 2026Article
- First-in-human PET study of [Journal of translational medicine · 2026Article
- Identification of a mechanism-based binding mode for a histone deacetylase 6 inhibitor.Nature communications · 2026Article
- Glycolytic lactylation modulates cell death decisions in diabetic kidney disease: Metabolic‑epigenetic interplay between ferroptosis and autophagy in fibrotic remodeling (Review).International journal of molecular medicine · 2026Review
- A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2026Article
- Fair and Square: Design, Synthesis and Biological Evaluations of Squaric Acid Derivatives as Novel HDAC8 Inhibitors.ChemMedChem · 2026Article
- Rapid photo-crosslinking in living cells reveals protein-nucleic acid dynamics on a timescale of minutes.Nucleic acids research · 2026Article
- Cellular Target Engagement and Dissociation Kinetics of Class I-Selective Histone Deacetylase (HDAC) Inhibitors.International journal of molecular sciences · 2026Article
- Recommended Tool Compounds: Isoform- and Class-Specific Histone Deacetylase Inhibitors.ACS pharmacology & translational science · 2026Review
- Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition.Communications biology · 2026Article
- Mapping drug mechanisms with ProteomicsDB: unified omics and cell sensitivity data at scale.Nucleic acids research · 2026Article
- Article
- Post-translational acylation of proteins in cardiac hypertrophy.Nature reviews. Cardiology · 2025Review
- Discovery of Pyrazole-Based Positron Emission Tomography Agent that Maps Histone Deacetylase 6 (HDAC6) in the Nonhuman Primate Brain.Journal of medicinal chemistry · 2025Article
- A First-in-Class Chemical-Induced Proximity System Achieves Dose-Dependent Control of Tumor Protein P53 Gene Activation in Preclinical Models of Gastric Cancer.ACS pharmacology & translational science · 2025Article
15 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
25 authors at 4 institutions in 2 countries.
Funding
Abstract
Drugs that target histone deacetylase (HDAC) entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9 of the 11 human zinc-dependent HDACs, questions the reported selectivity of some widely-used molecules (notably for HDAC6) and delineates how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-β-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent off-target of hydroxamate drugs. This poorly characterized palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nanomolar potency. MBLAC2 enzymatic inhibition and knockdown led to the accumulation of extracellular vesicles. Given the importance of extracellular vesicle biology in neurological diseases and cancer, this HDAC-independent drug effect may qualify MBLAC2 as a target for drug discovery.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.