PXD032671-1

PXD032671 is an original dataset announced via ProteomeXchange.

Title	Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation
Description	We report the first selective chemical probes for histone deacetylase 10 (HDAC10) with unprecedented selectivity over other HDAC isozymes. HDAC10 deacetylates polyamines and has a distinct substrate specificity, making it unique among the 11 zinc-dependent HDAC hydrolases. Taking inspiration from HDAC10 polyamine substrates, we systematically inserted an amino group (“aza-scan”) into the hexyl linker moiety of the approved drug Vorinostat (SAHA). This one atom replacement (C-->N) transformed SAHA from an unselective pan-HDAC inhibitor into a specific HDAC10 inhibitor. Optimization of the aza-SAHA structure yielded DKFZ-748, which has a double-digit nanomolar IC50 against HDAC10 in cells and >500-fold selectivity over the closest relative HDAC6 as well as the Class I enzymes (HDAC1, 2, 3, 8). The selectivity over other class I, IIb, IIa HDACs and common the off-targets MBLAC2, ISOC1/2, GATD3Aand ALDH2 was confirmed via chemotproteomic selecitivty profiling. Potency of our aza-SAHA derivatives is rationalized with HDAC10 co-crystal structures and demonstrated by cellular and biochemical target-engagement, as well as thermal-shift, assays. Treatment of cells with DKFZ-748, followed by quantification of selected polyamines, confirmed for the first time the suspected cellular function of HDAC10 as a poly-amine deacetylase. Selective HDAC10 chemical probes provide a valuable pharmacological tool for target validation and will enable further studies on the enigmatic biology of HDAC10 and acetylated polyamines. HDAC10-selective aza-SAHA derivatives are not cytotoxic, which opens the doors to novel therapeutic applications as immunomodulators or in combination cancer therapy.
HostingRepository	PRIDE
AnnounceDate	2026-06-02
AnnouncementXML	Submission_2026-06-02_03:38:14.329.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: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-20 15:39:50	ID requested
⏵ 1	2026-06-02 03:38:15	announced

10.1021/jacs.2c05030;

Steimbach RR, Herbst-Gervasoni CJ, Lechner S, Stewart TM, Klinke G, Ridinger J, G, é, raldy MNE, Tihanyi G, Foley JR, Uhrig U, Kuster B, Poschet G, Casero RA, M, é, dard G, Oehme I, Christianson DW, Gunkel N, Miller AK, Aza-SAHA Derivatives Are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation and Phenocopy HDAC10 Knockout. J Am Chem Soc, 144(41):18861-18875(2022) [pubmed]

submitter keyword: Histone Deacetylase, Polyamines, BE(2)-C, Drug Discovery,Chemical Proteomics, Chemical Biology, Chemical Probes, LC-MS/MS

Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, 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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/06/PXD032671

PRIDE project URI

• PRIDE
  1. PXD032671
     1. Label: PRIDE project
     2. Name: Aza-SAHA Derivatives are Selective Histone Deacetylase 10 Chemical Probes That Inhibit Polyamine Deacetylation