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PXD026657

PXD026657 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTarget deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target
DescriptionHDAC drugs have entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a chemical proteomics assay using three promiscuous chemotypes and quantitative mass spectrometry that we deployed to establish the target landscape of 56 HDAC drugs. The results highlight 14 direct targets, including 9 out of the 11 human zinc-dependent HDACs, question the reported selectivity of widely-used molecules, notably for HDAC6, and identified novel interactome-dependent binding of drugs to HDAC1/2 epigenetic complexes. Unexpectedly, metallo-beta-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent target of hydroxamate drugs. This ill-annotated palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nM potency. Both enzymatic inhibition and knocking down the protein led to the accumulation of extracellular vesicles. Given the importance of exosome biology in neurological diseases or cancer, this HDAC-independent drug effect creates the incentive for considering MBLAC2 as a target for drug discovery.
HostingRepositoryPRIDE
AnnounceDate2022-05-11
AnnouncementXMLSubmission_2022-05-11_07:59:40.298.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSeverin Lechner
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListTMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive HF; Orbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-06-11 07:24:48ID requested
12022-05-11 07:18:37announced
22022-05-11 07:59:41announced2022-05-11: Updated publication reference for PubMed record(s): 35484434.
Publication List
Lechner S, Malgapo MIP, Gr, ä, tz C, Steimbach RR, Baron A, R, ü, ther P, Nadal S, Stumpf C, Loos C, Ku X, Prokofeva P, Lautenbacher L, Heimburg T, W, ü, rf V, Meng C, Wilhelm M, Sippl W, Kleigrewe K, Pauling JK, Kramer K, Miller AK, Pfaffl MW, Linder ME, Kuster B, M, é, dard G, Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target. Nat Chem Biol, 18(8):812-820(2022) [pubmed]
Keyword List
submitter keyword: Human, Cancer cell lines, affinity pulldown, LC-MSMS, DDA
Contact List
Bernhard Kuster
contact affiliationChair of Proteomics and Bioanalytics, Technical University of Munich (TUM), 85354 Freising, Germany
contact emailkuster@tum.de
lab head
Severin Lechner
contact affiliationChair of proteomics and Bioanalytics, Technical Univerity Munich
contact emailseverin.lechner@tum.de
dataset submitter
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Dataset FTP location
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PRIDE project URI
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