Dataset Information

Hierarchical small molecule inhibition of MYST acetyltransferases

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cervical Epithelial Cell

DISEASE(S): Cervix Carcinoma

SUBMITTER: Kiall Francis Suazo

LAB HEAD: Jordan Leslie Meier

PROVIDER: PXD074488 | Pride | 2026-06-01

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	MQ_iBAQ_proteinGroups.txt	Txt
	Meier_230324_Chen_Lumos_TMTpro_H3K14.msf	Msf
	Meier_230324_Chen_Lumos_TMTpro_H3K14.raw	Raw
	Meier_230827_TMTpro_H3K14-PF_FAIMS-.msf	Msf
	Meier_230827_TMTpro_H3K14-PF_FAIMS-1.raw	Raw

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Publications

Hierarchical small molecule inhibition of MYST acetyltransferases.

Chen Xuemin X Castroverde Alexandra A Perez Minervo M Holewinski Ronald R Suazo Kiall F KF Karki Rashmi R Andresson Thorkell T Garcia Benjamin A BA Meier Jordan L JL

Nature communications 20260513 1

MYST lysine acetyltransferases (KATs) are 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 preclinical models as well as in clinical trials of breast cancer. Understanding the specificity of these molecules is critical for their effective use as chemical probes. Here we apply an integrated profiling strategy to systematically define the potency ...[more]

PMID: 42129151

Similar Datasets

Project description:Acetylation of histones by lysine acetyltransferases (KATs) is essential for chromatin organization and function. The MYST family of KATs (KAT5-8) includes the oncogenes KAT6A (MOZ) and KAT6B (MORF/QKF). KAT6A has essential roles in normal hematopoietic stem cells and is the target of recurrent chromosomal translocations, causing acute myeloid leukemia. Similarly, chromosomal translocations in KAT6B have been identified in diverse cancers. KAT6A suppresses cellular senescence via regulation of suppressors of the CDKN2A locus, a function that requires its KAT activity. Loss of one allele of KAT6A extends the median survival of mice with MYC-induced lymphoma from 105 to 413 days. These findings suggest that inhibition of KAT6A and KAT6B may provide a therapeutic benefit in cancer. We have produced a series of highly potent, selective inhibitors of KAT6A/B including WM-8014 and WM-1119. Biochemical and structural studies demonstrate that these compounds are reversible acetyl-CoA competitors and inhibit MYST-catalyzed histone acetylation. WM-8014 and WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF dependent and accompanied by gene expression changes typical of loss of KAT6A function. We anticipate that this class of inhibitors will be useful in accelerating development of therapeutics targeting gene transcription regulated by histone acetylation. We show that WM-1119 arrests lymphoma progression in mice. The B cell lymphoma cell line, EMRK1184, was isolated from Eμ-Myc transgenic mice, which are mice with a tumor resulting from the expression of cMyc under the control of the IgH enhancer. EMRK1184 expresses the Cdnk2a locus-encoded ARF and wild type p53. Treatment with WM-1119 inhibited the proliferation of the EMRK1184 lymphoma cells in vitro. RNA-seq and Western blot analysis showed that WM-1119 treatment resulted in increased levels of Cdkn2a and Cdkn2b mRNA and P16INK4a and p19ARF protein, as well as a delayed increase in Cdkn1a mRNA. The data here present RNA-seq profiling of EMRK1184 lymphomas treated with either WM-1119 or a control.