Synthesis and biological testing of novel pyridoisothiazolones as histone acetyltransferase inhibitors

Furdas, Silviya D.; Shekfeh, Suhaib; Bissinger, Elisabeth-Maria; Wagner, Julia M.; Schlimme, Sonja; Valkov, Vassil; Hendzel, Michael J.; Jung, Manfred; Sippl, Wolfgang

doi:10.1016/j.bmc.2011.01.063

Cited by 42 publications

(40 citation statements)

References 31 publications

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“…HAT inhibition by small synthetic pyridoisothiazolones has been previously investigated [15]. In this study, these potential HAT inhibitors were evaluated for the inhibition of the human HAT subtypes GCN5, p300 and CBP in vitro using an immobilized histone peptide substrate and a heterogeneous assay format.…”

Section: Resultsmentioning

confidence: 99%

“…For each treatment condition, 10 worm pairs were maintained in 60-mm diameter culture dishes in 2 mL of culture medium, supplemented with 10 nM to 50 µM PU139. The medium and the HAT inhibitor PU139 [15] were refreshed every 24 h during the treatment period (1–4 days). After treatment, the total RNA was extracted, and qRT-PCR was performed for the target genes (the oligonucleotides are listed in Table S2).…”

Section: Methodsmentioning

confidence: 99%

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Epigenetic Changes Modulate Schistosome Egg Formation and Are a Novel Target for Reducing Transmission of Schistosomiasis

et al. 2014

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Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A large fraction of the total mRNA in the mature female worm encodes one eggshell protein, Smp14. We report that the nuclear receptors SmRXR1 and SmNR1 regulate Smp14 transcription through the recruitment of two histone acetyltransferases (HATs), SmGCN5 and SmCBP1. The treatment of HEK293 cells with histone deacetylase (HDAC) inhibitors (NaB or TSA) produced an 8-fold activation of the SmRXR1/SmNR1-mediated Smp14 promoter activity. Incubation with synthetic HAT inhibitors, including PU139, significantly impaired the Smp14 promoter activity in these cells. Worm pairs cultivated in the presence of PU139 exhibited limited expression of Smp14 mRNA and protein. ChIP analysis demonstrated chromatin condensation at the Smp14 promoter site in worms treated with PU139. ChIP also revealed the presence of H3K27me3 and the absence of RNA Pol II at the Smp14 promoter region in the PU139-treated worms. Most significantly, the PU139-mediated inhibition of Smp14 expression resulted in a significant number of abnormal eggs as well as defective eggs within the ootype. In addition, scanning electron microscopy revealed structural defects and unformed eggshells, and vitelline cell leakage was apparent. The dsRNAi-targeting of SmGCN5 or SmCBP1 significantly decreased Smp14 transcription and protein synthesis, which compromised the reproductive system of mature female worms, egg-laying and egg morphology. Our data strongly suggest that the inhibition of Smp14 expression targeting SmGCN5 and/or SmCBP1 represents a novel and effective strategy to control S. mansoni egg development.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Epigenetic Changes Modulate Schistosome Egg Formation and Are a Novel Target for Reducing Transmission of Schistosomiasis

et al. 2014

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“…In contrast, HATs that modify side chain lysine residues have been extensively characterized at both the biochemical and structural levels, and this understanding has led to the development of HAT-specific inhibitors (33)(34)(35). The ternary structure of Naa50p bound to CoA and a peptide fragment of its native substrate reported here now provides the first molecular insights into the mechanism of substrate binding and possibly also catalysis used by this class of enzymes and provides a molecular scaffold for the design of NAT-specific inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Structure of a Ternary Naa50p (NAT5/SAN) N-terminal Acetyltransferase Complex Reveals the Molecular Basis for Substrate-specific Acetylation

Liszczak

Arnesen

Marmorstein

2011

Journal of Biological Chemistry

165

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Background:The human Naa50p N-terminal acetyltransferase acetylates proteins on the ␣-amino group of methionine residues to regulate genome integrity and has elevated activity in cancer. Results: We report the structure of the Naa50p⅐CoA⅐peptide complex and related biochemistry. Conclusion: We reveal the molecular basis for substrate-specific acetylation by Naa50p. Significance: We provide a molecular scaffold for the design of Naa50p-specific inhibitors with possible therapeutic applications.

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“…Among the inhibitors so far described are natural substances that promiscuously bind a variety of targets (Piaz et al, 2011), or isothiazolone covalent modifiers (Ghizzoni et al, 2009). These latter include the more recently developed pyridoisothiazolones that effectively inhibit cancer cell proliferation (Furdas et al, 2011). However, a potent, selective inhibitor of the HAT EP300, C646, has been developed that binds at the cofactor pocket and has pro-apoptotic effects on prostate cancer cells (Bowers et al, 2010).…”

Section: Post-translational Modifications Of Histonesmentioning

confidence: 99%

Epigenetic control of gene function in schistosomes: a source of therapeutic targets?

et al. 2014

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The discovery of the epigenetic regulation of gene expression has revolutionized both our understanding of how genomes function and approaches to the therapy of numerous pathologies. Schistosomes are metazoan parasites and as such utilize most, if not all the epigenetic mechanisms in play in their vertebrate hosts: histone variants, histone tail modifications, non-coding RNA and, perhaps, DNA methylation. Moreover, we are acquiring an increasing understanding of the ways in which these mechanisms come into play during the complex schistosome developmental program. In turn, interest in the actors involved in epigenetic mechanisms, particularly the enzymes that carry out epigenetic modifications of histones or nucleic acid, as therapeutic targets has been stimulated by the finding that their inhibitors exert profound effects, not only on survival, but also on the reproductive function of Schistosoma mansoni. Here, we review our current knowledge, and what we can infer, about the role of epigenetic mechanisms in schistosome development, differentiation and survival. We will consider which epigenetic actors can be targeted for drug discovery and what strategies can be employed to develop potent, selective inhibitors as drugs to cure schistosomiasis.

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Synthesis and biological testing of novel pyridoisothiazolones as histone acetyltransferase inhibitors

Cited by 42 publications

References 31 publications

Epigenetic Changes Modulate Schistosome Egg Formation and Are a Novel Target for Reducing Transmission of Schistosomiasis

Epigenetic Changes Modulate Schistosome Egg Formation and Are a Novel Target for Reducing Transmission of Schistosomiasis

Structure of a Ternary Naa50p (NAT5/SAN) N-terminal Acetyltransferase Complex Reveals the Molecular Basis for Substrate-specific Acetylation

Epigenetic control of gene function in schistosomes: a source of therapeutic targets?

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