Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors

Wagner, Florence F.; Weïwer, Michel; Steinbacher, Stefan; Schomburg, Adrian; Reinemer, Peter; Gale, Jennifer; Campbell, Arthur J.; Fisher, Stewart L.; Zhao, Wen-Ning; Reis, Surya A.; Hennig, Krista M.; Thomas, Melvin E.; Müller, Peter; Jefson, Martin R.; Fass, Daniel M.; Haggarty, Stephen J.; Zhang, Yanling; Holson, Edward B.

doi:10.1016/j.bmc.2016.06.040

Cited by 57 publications

(57 citation statements)

References 30 publications

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“…Most notably, the tyrosine in position 107 in HDAC 3 is a serine in HDAC 1 and 2, which is a difference that has been used to rationalize the identification of HDAC1/2 selective inhibitors [ 24 ]. In contrast to the serines in HDAC 1 and 2, the tyrosine 107 in HDAC3 provides steric hindrance for binding to the foot pocket, thus precluding binding of inhibitors with larger functional groups in this position [ 25 , 26 ]. Even deeper in the foot pocket in HDAC 1, 2, and 3, there are different hydrophobic amino acids at positions 29 and 13, thus providing small structural differences that could be employed for the development of selective binders [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

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The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Cao

Zwinderman

2018

Molecules

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Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future.

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Section: Resultsmentioning

confidence: 99%

“…Consequently, the K i value of the o -aminoanilides should be calculated from directly measured k on and k off values of the inhibitors, rather than through IC 50 values. This would provide a better indication of the selectivity profile of HDAC inhibition for this compound class [ 25 , 55 , 56 ].…”

Section: Resultsmentioning

confidence: 99%

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Cao

Zwinderman

2018

Molecules

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“…Besides varying in their isoform selectivity from the hydroxamates, CI-994 and Cpd-60 also differ in terms of their binding kinetics (Bantscheff et al, 2011, Lauffer et al, 2013, Wagner et al, 2016, Chou et al, 2008). Whereas hydroxamates have a fast-on/fast-off mechanism of action, CI-994 and Cpd-60 have a slow-on/slow-off mechanism of action (Schroeder et al, 2013, Chou et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

She

Kurtser

Reis

et al. 2017

Cell Chemical Biology

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Summary Frontotemporal dementia (FTD) arises from neurodegeneration in the frontal, insular, and anterior temporal lobes. Autosomal dominant causes of FTD include heterozygous mutations in the GRN gene causing haploinsufficiency of progranulin (PGRN) protein. Recently, histone deacetylase (HDAC) inhibitors have been identified as enhancers of PGRN expression, although the mechanisms through which GRN is epigenetically regulated remain poorly understood. Using a chemogenomic toolkit, including optoepigenetic probes, we show that inhibition of Class I HDACs is sufficient to upregulate PGRN in human neurons and only inhibitors with apparent fast binding to their target HDAC complexes are capable of enhancing PGRN expression. Moreover, we identify regions in the GRN promoter in which elevated H3K27 acetylation and transcription factor EB (TFEB) occupancy correlate with HDAC-inhibitor mediated upregulation of PGRN. These findings have implications for epigenetic and cis-regulatory mechanisms controlling human GRN expression and may advance translational efforts to develop targeted therapeutics for treating PGRN-deficient FTD.

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“…Much of our current understanding of the enzymatic properties of HDAC1 and LSD1 has come from studying these enzymes as purified proteins or in multi-protein complexes besides that of the purified core CoREST complex LSD1/HDAC1/CoREST1 (LHC) ( Hayward and Cole, 2016 ; López et al, 2016 ; Marabelli et al, 2016 ; Millard et al, 2013 ; 2017 ; Wagner et al, 2016 ; Watson et al, 2016 ). Until recently, it has been challenging to make purified, active LHC although an effective method for this has recently been described ( Kalin et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex

Hayward

Kalin

et al. 2018

eLife

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The core CoREST complex (LHC) contains histone deacetylase HDAC1 and histone demethylase LSD1 held together by the scaffold protein CoREST. Here, we analyze the purified LHC with modified peptide and reconstituted semisynthetic mononucleosome substrates. LHC demethylase activity toward methyl-Lys4 in histone H3 is strongly inhibited by H3 Lys14 acetylation, and this appears to be an intrinsic property of the LSD1 subunit. Moreover, the deacetylase selectivity of LHC unexpectedly shows a marked preference for H3 acetyl-Lys9 versus acetyl-Lys14 in nucleosome substrates but this selectivity is lost with isolated acetyl-Lys H3 protein. This diminished activity of LHC to Lys-14 deacetylation in nucleosomes is not merely due to steric accessibility based on the pattern of sensitivity of the LHC enzymatic complex to hydroxamic acid-mediated inhibition. Overall, these studies have revealed how a single Lys modification can confer a composite of resistance in chromatin to a key epigenetic enzyme complex involved in gene silencing.

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Kinetic and structural insights into the binding of histone deacetylase 1 and 2 (HDAC1, 2) inhibitors

Cited by 57 publications

References 30 publications

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia

Lysine-14 acetylation of histone H3 in chromatin confers resistance to the deacetylase and demethylase activities of an epigenetic silencing complex

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