Inhibitors of the Zinc‐Dependent Histone Deacetylases

Kristensen, Helle M. E.; Madsen, Andreas Stahl; Olsen, Christian A.

doi:10.1002/9783527809257.ch7

Cited by 7 publications

(14 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The cap group of such inhibitors interacts with the enzyme surface close to the catalytic pocket and the linker projects a zinc-binding group through a channel to the Zn 2+ ion in the active site (Figure 2A). 31,32 Consequently, the turnover of Kac-containing peptides by Zn 2+ -dependent HDACs can be inhibited by entities where the Kac has been substituted with zinc-binding groups and peptides containing the hydroxamic acid [32][33][34] or the o-aminoanilide 35 functionalities have been shown to bind and/or capture HDAC enzymes. Here, we explored the use of these moieties in histone tail peptide microarrays to interrogate binding of class I HDACs.…”

Section: Modified Peptides Enable Interrogation Of Hdac Binding In MImentioning

confidence: 99%

“…We found that replacing lysine residues on histone sequences by L-2-amino-8-(hydroxyamino)- compounds such as panobinostat. 31 We next envisioned that hydroxamic acid-modified peptide microarrays would enable the direct and simple interrogation of HDAC isozyme binding and, potentially, facilitate the development of isozyme-selective inhibitors and affinity probes ( Figure 1C). The implementation of this technique required an improved synthetic route for the Asuha building block.…”

Section: Modified Peptides Enable Interrogation Of Hdac Binding In MImentioning

confidence: 99%

“…(A) Approved drugs and examples of candidates in clinical trials that target class I HDACs. 31 Shared features include a cap group, a hydrophobic linker region, and zinc-binding group. (B) Display and probing of modified 15-mer histone peptides for capture of HDAC3 on microarray slides.…”

Section: Modified Peptides Enable Interrogation Of Hdac Binding In MImentioning

confidence: 99%

“…Multiple natural and synthetic inhibitors of class I HDACs (HDACs 1-3 and 8) have been reported, some of which are in clinical use. [30][31] The majority are small molecules bearing a hydroxamic acid modification, which exhibit limited isozyme selectivity. Microarray screening (Figures 3 and 4) identified modified peptides with potential isozyme selectivity and suggested that even small chemical modifications can exert strong and isozyme-selective effects on HDAC recognition.…”

Section: Identification Of Potent Hdac Inhibitors With Tailored Isozymentioning

confidence: 99%

“…[19][20][28][29] Despite these efforts, the understanding of the inhibitor and substrate selectivities of the human Zn 2+ -dependent HDAC isoforms is still incomplete. This is particularly true for class I HDACs (HDACs 1-3 and 8, Figure 1A), which are the HDAC isozymes primarily targeted by clinically used drugs [30][31] and responsible for histone deacetylation. 16 Here, we report the synthesis and application of peptide microarrays that circumvent the aforementioned limitations by introduction of hydroxamic acid-containing residues in place of the Kac residues ( Figure 1B), [32][33][34] which thereby provide a platform to dissect HDAC function in high-throughput ( Figure 1C).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Hydroxamic Acid-Modified Peptide Microarrays for Profiling Isozyme-Selective Interactions and Inhibition of Histone Deacetylases

Moreno–Yruela¹,

Vrsanova²,

Maric³

et al. 2020

Preprint

View full text Add to dashboard Cite

Histones control gene expression by regulating chromatin structure and function. The posttranslational modifications (PTMs) on the side chains of histones form the epigenetic landscape, which is tightly controlled through the enzymatic action of epigenetic effector proteins and protein complexes. Further, various PTM signatures or combinations are recognized by so-called reader domains. Histone microarrays have been widely applied to investigate such histone–reader interactions. So far, however, these could not be used to directly study the fast and transient interactions of Zn<sup>2+</sup>-dependent histone deacetylase (HDAC) enzymes. Here, we describe the synthesis of hydroxamic acid-modified histone-derived peptides and their use in femtomolar microarrays for the direct capture and detection of the four class I HDAC isozymes. We further demonstrate their suitability to discover and map HDAC isozyme-specific substrates. Functional assays confirmed the prediction of HDAC–peptide binding requirements and the conversion of acetylated substrates in response to PTMs and mutations. Subsequent analysis of the hydroxamic acid-containing peptides identified compounds with nanomolar potency and unanticipated selectivity. Follow-up analyses confirmed a major contribution of the peptide sequence to substrate turnover, inhibitor potency, and isozyme selectivity. We conclude that similar hydroxamic acid-modified histone peptide microarrays and libraries could find broad application to identify class I HDAC isozyme-specific substrates and facilitate the development of isozyme- or protein complex-selective HDAC inhibitors and affinity probes.

show abstract

Section: Modified Peptides Enable Interrogation Of Hdac Binding In MImentioning

confidence: 99%

Section: Modified Peptides Enable Interrogation Of Hdac Binding In MImentioning

confidence: 99%

Section: Modified Peptides Enable Interrogation Of Hdac Binding In MImentioning

confidence: 99%

Section: Identification Of Potent Hdac Inhibitors With Tailored Isozymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Hydroxamic Acid-Modified Peptide Microarrays for Profiling Isozyme-Selective Interactions and Inhibition of Histone Deacetylases

Moreno–Yruela¹,

Vrsanova²,

Maric³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity

Moreno–Yruela

Olsen

2022

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

Histone deacetylases (HDACs) 1−3 regulate chromatin structure and gene expression. These three enzymes are targets for cancer chemotherapy and have been studied for the treatment of immune disorders and neurodegeneration, but there is a lack of selective pharmacological tool compounds to unravel their individual roles. Potent inhibitors of HDACs 1−3 often display slow-binding kinetics, which causes a delay in inhibitor−enzyme equilibration and may affect assay readout. Here we compare the potencies and selectivities of slow-binding inhibitors measured by discontinuous and continuous assays. We find that entinostat, a clinical candidate, inhibits HDACs 1−3 by a two-step slow-binding mechanism with lower potencies than previously reported. In addition, we show that RGFP966, commercialized as an HDAC3-selective probe, is a slow-binding inhibitor with inhibitor constants of 57, 31, and 13 nM against HDACs 1−3, respectively. These data highlight the need for thorough kinetic investigation in the development of selective HDAC probes.

show abstract

Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases

et al. 2021

Self Cite

View full text Add to dashboard Cite

Histones control gene expression by regulating chromatin structure and function. The posttranslational modifications (PTMs) on the side chains of histones form the epigenetic landscape, which is tightly controlled by epigenetic modulator enzymes and further recognized by so-called reader domains. Histone microarrays have been widely applied to investigate histone–reader interactions, but not the transient interactions of Zn2+-dependent histone deacetylase (HDAC) eraser enzymes. Here, we synthesize hydroxamic acid-modified histone peptides and use them in femtomolar microarrays for the direct capture and detection of the four class I HDAC isozymes. Follow-up functional assays in solution provide insights into their suitability to discover HDAC substrates and inhibitors with nanomolar potency and activity in cellular assays. We conclude that similar hydroxamic acid-modified histone peptide microarrays and libraries could find broad application to identify class I HDAC isozyme-specific substrates and facilitate the development of isozyme-selective HDAC inhibitors and probes.

show abstract

Inhibitors of the Zinc‐Dependent Histone Deacetylases

Cited by 7 publications

References 74 publications

Hydroxamic Acid-Modified Peptide Microarrays for Profiling Isozyme-Selective Interactions and Inhibition of Histone Deacetylases

Hydroxamic Acid-Modified Peptide Microarrays for Profiling Isozyme-Selective Interactions and Inhibition of Histone Deacetylases

Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity

Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases

Contact Info

Product

Resources

About