PXD026657
PXD026657 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target |
Description | HDAC 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. |
HostingRepository | PRIDE |
AnnounceDate | 2022-05-11 |
AnnouncementXML | Submission_2022-05-11_07:59:40.298.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Severin Lechner |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive HF; Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2021-06-11 07:24:48 | ID requested | |
1 | 2022-05-11 07:18:37 | announced | |
⏵ 2 | 2022-05-11 07:59:41 | announced | 2022-05-11: 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 affiliation | Chair of Proteomics and Bioanalytics, Technical University of Munich (TUM), 85354 Freising, Germany |
contact email | kuster@tum.de |
lab head | |
Severin Lechner | |
contact affiliation | Chair of proteomics and Bioanalytics, Technical Univerity Munich |
contact email | severin.lechner@tum.de |
dataset submitter |
Full Dataset Link List
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PRIDE project URI |
Repository Record List
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