PXD026657

PXD026657 is an original dataset announced via ProteomeXchange.

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

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.

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]

submitter keyword: Human, Cancer cell lines, affinity pulldown, LC-MSMS, DDA

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

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PRIDE project URI

• PRIDE
  1. PXD026657
     1. Label: PRIDE project
     2. Name: Target deconvolution of HDAC pharmacopoeia highlights MBLAC2 as common off-target