Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

Furdas, Silviya D.; Hoffmann, Inga; Robaa, Dina; Herquel, Benjamin; Malinka, Wiesław; Świątek, Piotr; Akhtar, Asifa; Sippl, Wolfgang; Jung, Manfred

doi:10.1039/c4md00245h

Cited by 16 publications

(6 citation statements)

References 17 publications

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“…Nevertheless, growth inhibition in prostate cancer cells (LNCaP, GI50 ~36-37 µM) as well as leukemic cells (HL-60, GI50 ~3-4 µM) was elicited to the same extent [113]. was further used as a tool compound to decipher the differential roles of CBP and p300 in TCF/β-catenin-mediated survivin gene expression [122].…”

Section: Pyridoisothiazolones Pu139 -Pan-hat and Pu141 -P300/cbpmentioning

confidence: 99%

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

Richters

Koehler

2017

CMC

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Histone acetyltransferases (HATs) are epigenetic drivers that catalyze the acetyl transfer from acetyl-CoA to lysines of both histone and non-histone substrates and thereby induce transcription either by chromatin remodeling or direct transcription factor activation. Histone deacetylases (HDACs) conduct the reverse reaction to counter HAT activity. Physiological processes such as cell cycle progression or apoptosis require a thoroughly balanced equilibrium of the interplay between acetylation and deacetylation processes to maintain or, if required, alter the global acetylome status. Aberrant HAT activity has recently been demonstrated to play a crucial role in the progression of various diseases such as prostate, lung, and colon cancers as well as glioblastomas and neurodegenerative diseases. Recent investigations have aimed for the identification of HAT modulators to further decipher the complexity of acetyl transferase related signaling cascades and discover potential leads for drug design approaches. HDACs have been extensively characterized and targeted by small molecules, including four FDA-approved HDAC inhibitors; in contrast, HATs have not been active targets for therapeutic development. This review will summarize the status of HAT associated diseases and the arsenal of currently known and available HAT inhibitors with respect to their discovery, further improvements, and current applications.

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Section: Pyridoisothiazolones Pu139 -Pan-hat and Pu141 -P300/cbpmentioning

confidence: 99%

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

Richters

Koehler

2017

CMC

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“…N-Aryl substituted compounds were shown to cause pan-KAT inhibition on a series of enzymes (PCAF, Gcn5, p300, CBP, and MOF), while N-benzyl or N-alkyl substituents led to defined subtype selectivity patterns. 137 The Fantappie group incubated Schistosoma mansoni parasites with the compound 12.2 (PU139) and reported impaired promoter activity of the egg shell protein Smp14, probably evidently as a result of diminished SmGCN5 and SmCBP1 activity. 138 The repression of Smp14 controlled gene products led to production of abnormal and defective eggs, implying KAT inhibition as novel strategy in the control of schistosomiasis.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…Structure–activity studies revealed a crucial role of the substituent in 2-position for inhibitory activity. N -Aryl substituted compounds were shown to cause pan-KAT inhibition on a series of enzymes (PCAF, Gcn5, p300, CBP, and MOF), while N -benzyl or N -alkyl substituents led to defined subtype selectivity patterns . The Fantappie group incubated Schistosoma mansoni parasites with the compound 12.2 (PU139) and reported impaired promoter activity of the egg shell protein Smp14, probably evidently as a result of diminished SmGCN5 and SmCBP1 activity .…”

Section: Kat Modulatorsmentioning

confidence: 99%

KATching-Up on Small Molecule Modulators of Lysine Acetyltransferases

et al. 2016

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The reversible acetylation of lysines is one of the best characterized epigenetic modifications. Its involvement in many key physiological and pathological processes has been documented in numerous studies. Lysine deacetylases (KDACs) and acetyltransferases (KATs) maintain the acetylation equilibrium at histones but also many other proteins. Besides acetylation, also other acyl groups are reversibly installed at the side chain of lysines in proteins. Because of their involvement in disease, KDACs and KATs were proposed to be promising drug targets, and for KDACs, indeed, five inhibitors are now approved for human use. While there is a similar level of evidence for the potential of KATs as drug targets, no inhibitor is in clinical trials. Here, we review the evidence for the diverse roles of KATs in disease pathology, provide an overview of structural features and the available modulators, including those targeting the bromodomains of KATs, and present an outlook.

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“…Certainly continued vigilance will be required as BITZ compounds and their derivatives progress in development, with continued monitoring for potential promiscuous and off-target reactivity that may lead to toxicity. However, it should be noted that, similar BITZ chemotypes have demonstrated successful medicinal chemistry optimisation36373839404142. Recently, a molecule containing a BITZ moiety has begun Phase II clinical trials as an antiviral agent, providing important evidence that the potential reactivity of the BITZ moiety alone is not incompatible with a safe therapeutic profile43.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD

Price

Armstrong

Imlay

et al. 2016

Sci Rep

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The methylerythritol phosphate (MEP) pathway is an essential metabolic pathway found in malaria parasites, but absent in mammals, making it a highly attractive target for the discovery of novel and selective antimalarial therapies. Using high-throughput screening, we have identified 2-phenyl benzo[d]isothiazol-3(2H)-ones as species-selective inhibitors of Plasmodium spp. 2-C-methyl-D-erythritol-4-phosphate cytidyltransferase (IspD), the third catalytic enzyme of the MEP pathway. 2-Phenyl benzo[d]isothiazol-3(2H)-ones display nanomolar inhibitory activity against P. falciparum and P. vivax IspD and prevent the growth of P. falciparum in culture, with EC50 values below 400 nM. In silico modeling, along with enzymatic, genetic and crystallographic studies, have established a mechanism-of-action involving initial non-covalent recognition of inhibitors at the IspD binding site, followed by disulfide bond formation through attack of an active site cysteine residue on the benzo[d]isothiazol-3(2H)-one core. The species-selective inhibitory activity of these small molecules against Plasmodium spp. IspD and cultured parasites suggests they have potential as lead compounds in the pursuit of novel drugs to treat malaria.

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Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

Cited by 16 publications

References 17 publications

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

Epigenetic Modulation Using Small Molecules - Targeting Histone Acetyltransferases in Disease

KATching-Up on Small Molecule Modulators of Lysine Acetyltransferases

Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD

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