PXD074488

PXD074488 is an original dataset announced via ProteomeXchange.

Title	Hierarchical small molecule inhibition of MYST acetyltransferases
Description	MYST lysine acetyltransferases (KATs) is a class of epigenetic enzymes critical for cellular function that constitute an emerging therapeutic target in cancer. Recently, several drug-like MYST inhibitors have been reported that show promise in a variety of preclinical models as well as in clinical trials of breast cancer. However, the comparative properties of these small molecules remain to be directly assessed. Here we apply an integrated profiling strategy to systematically define the potency and selectivity of drug-like MYST KAT inhibitors. First, we use optimized chemoproteomic profiling and histone acetylation biormarkers to study the industry-developed KAT inhibitor PF-9363. This revealed dose-dependent engagement of native KAT complexes, with hierarchical inhibition following the order KAT6A/B > KAT7 >> KAT8 > KAT5. Next, we demonstrate how PF-9363s ability to disrupt capture of MYST complex members in chemoproteomic experiments can be leveraged identify new candidate members of these complexes, including the transcription factor FOXK2. Applying insights from these studies to WM-8014, WM-1119 and WM-3835, which have been extensively applied in the literature as MYST probes, highlights unexpected cross-inhibition and suggests a new framework for how these small molecules and biomarkers may be applied to differentiate KAT6A/B and KAT7-dependent phenotypes. Finally, we benchmark the activity of PF-9363 in the NCI-60 cell line screen, providing evidence that its ability to inhibit the growth of cell lines that are resistant to other KAT inhibitors may derive from engagement of the essential KAT8 enzyme at high concentrations. Collectively, our studies indicate the potential for MYST KAT inhibitors to exhibit dose-dependent target engagement reminiscent of kinase inhibitors and specify assays and biomarkers for facile monitoring of selective and hierarchical effects.
HostingRepository	PRIDE
AnnounceDate	2026-06-01
AnnouncementXML	Submission_2026-05-31_16:08:26.773.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kiall Francis Suazo
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2026-02-14 16:20:17	ID requested
⏵ 1	2026-05-31 16:08:27	announced

10.1038/s41467-026-70574-1;

Chen X, Castroverde A, Perez M, Holewinski R, Suazo KF, Karki R, Andresson T, Garcia BA, Meier JL, Hierarchical small molecule inhibition of MYST acetyltransferases. Nat Commun, 17(1):(2026) [pubmed]

submitter keyword: histone acetylation,Lysine acetyltransferases, WM-1119, WM-3835, drug-like MYST inhibitors, chemoproteomics, MYST, FOXK2, PF-9363, WM-8014

Jordan Leslie Meier
contact affiliation	Chemical Biology Laboratory, National Cancer Institute
contact email	jordan.meier@nih.gov
lab head
Kiall Francis Suazo
contact affiliation	Frederick National Laboratory
contact email	kiall.suazo@nih.gov
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD074488
     1. Label: PRIDE project
     2. Name: Hierarchical small molecule inhibition of MYST acetyltransferases