|
Antitrypanosomal activity against Trypanosoma brucei brucei 427 assessed as inhibition of parasite proliferation measured as ATP levels after 48 hrs by luciferase-based assay
|
Trypanosoma brucei brucei
|
29.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC1
|
Homo sapiens
|
0.03
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC2
|
Homo sapiens
|
0.06
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC3
|
Homo sapiens
|
2.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC8
|
Homo sapiens
|
0.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC4
|
Homo sapiens
|
0.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC5
|
Homo sapiens
|
2.1
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC7
|
Homo sapiens
|
66.6
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC9
|
Homo sapiens
|
3.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC6
|
Homo sapiens
|
16.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC10
|
Homo sapiens
|
0.05
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of human HDAC11
|
Homo sapiens
|
0.07
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).
Year : 2015
Volume : 23
Issue : 16
First Page : 5151
Last Page : 5155
Authors : Carrillo AK, Guiguemde WA, Guy RK.
Abstract : Two of the histone deacetylases, TbDAC1 and TbDAC3, have been reported to be essential genes in trypanosomes. Therefore, we tested the activity of a panel of human histone deacetylase inhibitors (HDACi) for their ability to block proliferation of Trypanosoma brucei brucei. Among the HDACi's, the hydroxamic acid derivatives panobinostat and belinostat exhibited potency that appeared to make them viable candidates for development due to their reported pharmacokinetic characteristics. However, cellular pharmacodynamic analysis demonstrated that these drugs were unable to kill cultured parasites at exposures seen in patients at their tolerated doses and additionally failed to show any synergistic effects in combination with pentamidine, suramin, melarsoprol, or nifurtimox. Analysis of the potency of the entire HDACi panel revealed no correlations between potency against any human HDAC isoform and inhibition of T. brucei proliferation, suggesting that the trypanosome histone deacetylases possess a unique specificity. These studies confirmed that HDAC inhibitors have potential as leads against human African trypanosomiasis but that none of the current clinical candidates can be directly repurposed. Therefore, development of HDACi's with appropriate specificity and potency may be a viable route to a new class of anti-trypanosomal drugs.
|
Inhibition of full length recombinant human HDAC1 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis
|
Homo sapiens
|
0.11
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease.
Year : 2016
Volume : 59
Issue : 19
First Page : 8967
Last Page : 9004
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).
|
Inhibition of full length recombinant human HDAC2 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis
|
Homo sapiens
|
0.33
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease.
Year : 2016
Volume : 59
Issue : 19
First Page : 8967
Last Page : 9004
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).
|
Inhibition of full length recombinant human HDAC3/NCOR2 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis
|
Homo sapiens
|
4.86
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease.
Year : 2016
Volume : 59
Issue : 19
First Page : 8967
Last Page : 9004
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).
|
Inhibition of full length recombinant human HDAC6 expressed in baculovirus infected Sf9 cells using RHKK-Ac as substrate by fluorescence analysis
|
Homo sapiens
|
76.8
nM
|
|
Journal : J Med Chem
Title : Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer's Disease.
Year : 2016
Volume : 59
Issue : 19
First Page : 8967
Last Page : 9004
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : Simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases (HDAC) has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). To further extend this concept, we designed and synthesized the first chemical series of dual acting PDE5 and HDAC inhibitors, and we validated this systems therapeutics approach. Following the implementation of structure- and knowledge-based approaches, initial hits were designed and were shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain a proper tool compound for in vivo testing in AD models. Initial hits were translated into molecules with adequate cellular functional responses (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation in the nanomolar range), an acceptable therapeutic window (>1 log unit), and the ability to cross the blood-brain barrier, leading to the identification of 7 as a candidate for in vivo proof-of-concept testing ( Cuadrado-Tejedor, M.; Garcia-Barroso, C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.; Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016 , in press, doi: 10.1038/npp.2016.163 ).
|
Inhibition of recombinant human LTA4H aminopeptidase activity expressed in Escherichia coli BL21 (DE3) pLysS assessed as formation of p-NA from Ala-p-NA at 10 uM preincubated for 10 mins followed by substrate addition measured after 10 mins
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 Biosynthesis.
Year : 2017
Volume : 60
Issue : 5
First Page : 1817
Last Page : 1828
Authors : Lu W, Yao X, Ouyang P, Dong N, Wu D, Jiang X, Wu Z, Zhang C, Xu Z, Tang Y, Zou S, Liu M, Li J, Zeng M, Lin P, Cheng F, Huang J.
Abstract : Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Importantly, both 1 and 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were determined in vivo. Collectively, 1 and 2 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
|
Inhibition of recombinant human LTA4H Epoxide Hydrolase expressed in Escherichia coli BL21 (DE3) pLysS at 10 uM preincubated for 10 mins followed by addition of LTA4 as substrate measured after 15 mins by reverse-phase HPLC analysis
|
Homo sapiens
|
50.0
%
|
|
Journal : J Med Chem
Title : Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 Biosynthesis.
Year : 2017
Volume : 60
Issue : 5
First Page : 1817
Last Page : 1828
Authors : Lu W, Yao X, Ouyang P, Dong N, Wu D, Jiang X, Wu Z, Zhang C, Xu Z, Tang Y, Zou S, Liu M, Li J, Zeng M, Lin P, Cheng F, Huang J.
Abstract : Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analogue 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Importantly, both 1 and 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were determined in vivo. Collectively, 1 and 2 would provide promising agents with well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
|
Inhibition of Schistosoma mansoni His-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method
|
Schistosoma mansoni
|
303.4
nM
|
|
Journal : J Med Chem
Title : Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Year : 2018
Volume : 61
Issue : 22
First Page : 10000
Last Page : 10016
Authors : Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, Da Veiga C, Kalinin D, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce RJ, Jung M, Sippl W, Romier C.
Abstract : Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
|
Inhibition of human His-thioredoxin-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method
|
Homo sapiens
|
64.4
nM
|
|
Journal : J Med Chem
Title : Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Year : 2018
Volume : 61
Issue : 22
First Page : 10000
Last Page : 10016
Authors : Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, Da Veiga C, Kalinin D, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce RJ, Jung M, Sippl W, Romier C.
Abstract : Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
|
Binding affinity to human His-thioredoxin-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells by ITC method
|
Homo sapiens
|
22.7
nM
|
|
Journal : J Med Chem
Title : Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Year : 2018
Volume : 61
Issue : 22
First Page : 10000
Last Page : 10016
Authors : Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, Da Veiga C, Kalinin D, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce RJ, Jung M, Sippl W, Romier C.
Abstract : Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
|
Binding affinity to Schistosoma mansoni His-tagged HDAC8 expressed in Escherichia coli BL21 (DE3) cells by ITC method
|
Schistosoma mansoni
|
28.4
nM
|
|
Journal : J Med Chem
Title : Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Year : 2018
Volume : 61
Issue : 22
First Page : 10000
Last Page : 10016
Authors : Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, Da Veiga C, Kalinin D, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce RJ, Jung M, Sippl W, Romier C.
Abstract : Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
|
Inhibition of human His-thioredoxin-tagged HDAC8 mL6 mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method
|
Homo sapiens
|
93.0
nM
|
|
Journal : J Med Chem
Title : Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Year : 2018
Volume : 61
Issue : 22
First Page : 10000
Last Page : 10016
Authors : Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, Da Veiga C, Kalinin D, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce RJ, Jung M, Sippl W, Romier C.
Abstract : Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
|
Inhibition of human His-thioredoxin-tagged HDAC8 mL1/mL6 mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method
|
Homo sapiens
|
94.0
nM
|
|
Journal : J Med Chem
Title : Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Year : 2018
Volume : 61
Issue : 22
First Page : 10000
Last Page : 10016
Authors : Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, Da Veiga C, Kalinin D, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce RJ, Jung M, Sippl W, Romier C.
Abstract : Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
|
Inhibition of human His-thioredoxin-tagged HDAC8 mL6/L179I mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method
|
Homo sapiens
|
169.0
nM
|
|
Journal : J Med Chem
Title : Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Year : 2018
Volume : 61
Issue : 22
First Page : 10000
Last Page : 10016
Authors : Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, Da Veiga C, Kalinin D, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce RJ, Jung M, Sippl W, Romier C.
Abstract : Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
|
Inhibition of human His-thioredoxin-tagged HDAC8 mL1/mL6/L179I mutant expressed in Escherichia coli BL21 (DE3) cells using Fluor de Lys (R)-HDAC8 as substrate by fluorometric method
|
Homo sapiens
|
217.0
nM
|
|
Journal : J Med Chem
Title : Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants.
Year : 2018
Volume : 61
Issue : 22
First Page : 10000
Last Page : 10016
Authors : Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, Da Veiga C, Kalinin D, Melesina J, Robaa D, Schmidtkunz K, Suzuki T, Holl R, Ennifar E, Pierce RJ, Jung M, Sippl W, Romier C.
Abstract : Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet the currently FDA-approved HDAC inhibitors nonspecifically target at least several of the 11 structurally similar but functionally different HDAC isozymes, which hampers their broad usage in clinical settings. Selective inhibitors targeting single HDAC isozymes are being developed, but precise understanding in molecular terms of their selectivity remains sparse. Here, we show that HDAC8-selective inhibitors adopt a L-shaped conformation required for their binding to a HDAC8-specific pocket formed by HDAC8 catalytic tyrosine and HDAC8 L1 and L6 loops. In other HDAC isozymes, a L1-L6 lock sterically prevents L-shaped inhibitor binding. Shielding of the HDAC8-specific pocket by protein engineering decreases potency of HDAC8-selective inhibitors and affects catalytic activity. Collectively, our results unravel key HDAC8 active site structural and functional determinants important for the design of next-generation chemical probes and epigenetic drugs.
|
Inhibition of human recombinant HDAC1 using Fluor de Lys as substrate after 2 hrs by fluorescence method
|
Homo sapiens
|
0.48
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Pro-apoptotic activity in human HUT78 cells after 18 hrs by caspase-Glo 3/7 assay
|
Homo sapiens
|
6.5
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC1 using fluorogenic HDAC substrate after 15 mins by fluorimetrc method
|
Homo sapiens
|
7.3
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC2 using fluorogenic HDAC substrate after 15 mins by fluorimetrc method
|
Homo sapiens
|
31.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC3 using fluorogenic HDAC substrate after 10 mins by spectrophotometric method
|
Homo sapiens
|
4.3
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC8 using fluorogenic HDAC substrate after 15 mins by fluorimetrc method
|
Homo sapiens
|
24.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC4 using fluorogenic HDAC substrate class 2a after 30 mins by fluorimetrc method
|
Homo sapiens
|
6.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC5 using fluorogenic HDAC substrate class 2a after 30 mins by fluorimetrc method
|
Homo sapiens
|
4.3
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC7 using fluorogenic HDAC substrate class 2a after 45 mins by fluorimetrc method
|
Homo sapiens
|
1.7
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC9 using fluorogenic HDAC substrate class 2a after 30 mins by fluorimetrc method
|
Homo sapiens
|
5.3
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC6 using fluorogenic HDAC substrate after 30 mins by fluorimetrc method
|
Homo sapiens
|
350.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of human recombinant HDAC10 using fluorogenic HDAC substrate after 45 mins by fluorimetrc method
|
Homo sapiens
|
4.4
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.
Year : 2018
Volume : 28
Issue : 17
First Page : 2985
Last Page : 2992
Authors : Fournier JF, Bhurruth-Alcor Y, Musicki B, Aubert J, Aurelly M, Bouix-Peter C, Bouquet K, Chantalat L, Delorme M, Drean B, Duvert G, Fleury-Bregeot N, Gauthier B, Grisendi K, Harris CS, Hennequin LF, Isabet T, Joly F, Lafitte G, Millois C, Morgentin R, Pascau J, Piwnica D, Rival Y, Soulet C, Thoreau É, Tomas L.
Abstract : A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.
|
Inhibition of recombinant full length human HDAC1 expressed in baculovirus infected Sf9 cells using FAM-RHKK-Ac as substrate incubated for 17 hrs by electrophoretic mobility shift assay
|
Homo sapiens
|
0.617
nM
|
|
Journal : ACS Med Chem Lett
Title : Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
Year : 2020
Volume : 11
Issue : 1
First Page : 56
Last Page : 64
Authors : Shouksmith AE, Gawel JM, Nawar N, Sina D, Raouf YS, Bukhari S, He L, Johns AE, Manaswiyoungkul P, Olaoye OO, Cabral AD, Sedighi A, de Araujo ED, Gunning PT.
Abstract : The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
|
Inhibition of recombinant full length human HDAC2 expressed in baculovirus infected Sf9 cells using FAM-RHKK-Ac as substrate incubated for 17 hrs by electrophoretic mobility shift assay
|
Homo sapiens
|
2.16
nM
|
|
Journal : ACS Med Chem Lett
Title : Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
Year : 2020
Volume : 11
Issue : 1
First Page : 56
Last Page : 64
Authors : Shouksmith AE, Gawel JM, Nawar N, Sina D, Raouf YS, Bukhari S, He L, Johns AE, Manaswiyoungkul P, Olaoye OO, Cabral AD, Sedighi A, de Araujo ED, Gunning PT.
Abstract : The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
|
Inhibition of recombinant full length human HDAC4 expressed in baculovirus infected Sf9 cells using FAM-RHKK-TFAc as substrate incubated for 1.5 hrs by electrophoretic mobility shift assay
|
Homo sapiens
|
4.61
nM
|
|
Journal : ACS Med Chem Lett
Title : Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
Year : 2020
Volume : 11
Issue : 1
First Page : 56
Last Page : 64
Authors : Shouksmith AE, Gawel JM, Nawar N, Sina D, Raouf YS, Bukhari S, He L, Johns AE, Manaswiyoungkul P, Olaoye OO, Cabral AD, Sedighi A, de Araujo ED, Gunning PT.
Abstract : The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
|
Inhibition of recombinant full length human HDAC5 expressed in baculovirus infected Sf9 cells using FAM-RHKK-TFAc as substrate incubated for 3 hrs by electrophoretic mobility shift assay
|
Homo sapiens
|
5.95
nM
|
|
Journal : ACS Med Chem Lett
Title : Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
Year : 2020
Volume : 11
Issue : 1
First Page : 56
Last Page : 64
Authors : Shouksmith AE, Gawel JM, Nawar N, Sina D, Raouf YS, Bukhari S, He L, Johns AE, Manaswiyoungkul P, Olaoye OO, Cabral AD, Sedighi A, de Araujo ED, Gunning PT.
Abstract : The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
|
Inhibition of recombinant full length human HDAC7 expressed in baculovirus infected Sf9 cells using FAM-RHKK-TFAc as substrate incubated for 3 hrs by electrophoretic mobility shift assay
|
Homo sapiens
|
4.04
nM
|
|
Journal : ACS Med Chem Lett
Title : Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
Year : 2020
Volume : 11
Issue : 1
First Page : 56
Last Page : 64
Authors : Shouksmith AE, Gawel JM, Nawar N, Sina D, Raouf YS, Bukhari S, He L, Johns AE, Manaswiyoungkul P, Olaoye OO, Cabral AD, Sedighi A, de Araujo ED, Gunning PT.
Abstract : The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
|
Inhibition of recombinant human HDAC9 (604-1066 residues) expressed in baculovirus infected Sf9 cells using FAM-RHKK-TFAc as substrate incubated for 3 hrs by electrophoretic mobility shift assay
|
Homo sapiens
|
6.7
nM
|
|
Journal : ACS Med Chem Lett
Title : Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
Year : 2020
Volume : 11
Issue : 1
First Page : 56
Last Page : 64
Authors : Shouksmith AE, Gawel JM, Nawar N, Sina D, Raouf YS, Bukhari S, He L, Johns AE, Manaswiyoungkul P, Olaoye OO, Cabral AD, Sedighi A, de Araujo ED, Gunning PT.
Abstract : The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
|
Inhibition of recombinant full length human HDAC10 expressed in baculovirus infected Sf9 cells using FAM-RHKK-Ac as substrate incubated for 17 hrs by electrophoretic mobility shift assay
|
Homo sapiens
|
1.96
nM
|
|
Journal : ACS Med Chem Lett
Title : Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
Year : 2020
Volume : 11
Issue : 1
First Page : 56
Last Page : 64
Authors : Shouksmith AE, Gawel JM, Nawar N, Sina D, Raouf YS, Bukhari S, He L, Johns AE, Manaswiyoungkul P, Olaoye OO, Cabral AD, Sedighi A, de Araujo ED, Gunning PT.
Abstract : The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
|
Inhibition of tubastatin-Alexa647-tracer binding to recombinant GST-tagged HDAC10 (unknown origin) measured after 1 hr by TR-FRET assay
|
Homo sapiens
|
10.0
nM
|
|
Journal : J Med Chem
Title : Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated.
Year : 2019
Volume : 62
Issue : 9
First Page : 4426
Last Page : 4443
Authors : Géraldy M, Morgen M, Sehr P, Steimbach RR, Moi D, Ridinger J, Oehme I, Witt O, Malz M, Nogueira MS, Koch O, Gunkel N, Miller AK.
Abstract : The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.
|
Inhibition of dye-labeled tracer binding to HDAC10 (unknown origin) transfected in human HeLa cells measured after 2 hrs by nano-luciferase reporter gene-based BRET assay
|
Homo sapiens
|
39.81
nM
|
|
Journal : J Med Chem
Title : Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated.
Year : 2019
Volume : 62
Issue : 9
First Page : 4426
Last Page : 4443
Authors : Géraldy M, Morgen M, Sehr P, Steimbach RR, Moi D, Ridinger J, Oehme I, Witt O, Malz M, Nogueira MS, Koch O, Gunkel N, Miller AK.
Abstract : The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.
|
Inhibition of HDAC1 (unknown origin)
|
Homo sapiens
|
4.26
nM
|
|
Journal : Eur J Med Chem
Title : Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overview.
Year : 2019
Volume : 164
First Page : 214
Last Page : 240
Authors : Banerjee S, Adhikari N, Amin SA, Jha T.
Abstract : The histone deacetylases (HDACs) enzymes provided crucial role in transcriptional regulation of cells through deacetylation of nuclear histone proteins. Discoveries related to the HDAC8 enzyme activity signified the importance of HDAC8 isoform in cell proliferation, tumorigenesis, cancer, neuronal disorders, parasitic/viral infections and other epigenetic regulations. The pan-HDAC inhibitors can confront these conditions but have chances to affect epigenetic functions of other HDAC isoforms. Designing of selective HDAC8 inhibitors is a key feature to combat the pathophysiological and diseased conditions involving the HDAC8 activity. This review is concerned about the structural and positional aspects of HDAC8 in the HDAC family. It also covers the contributions of HDAC8 in the pathophysiological conditions, a preliminary discussion about the recent scenario of HDAC8 inhibitors. This review might help to deliver the structural, functional and computational information in order to identify and design potent and selective HDAC8 inhibitors for target specific treatment of diseases involving HDAC8 enzymatic activity.
|
Inhibition of HDAC2 (unknown origin)
|
Homo sapiens
|
4.26
nM
|
|
Journal : Eur J Med Chem
Title : Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overview.
Year : 2019
Volume : 164
First Page : 214
Last Page : 240
Authors : Banerjee S, Adhikari N, Amin SA, Jha T.
Abstract : The histone deacetylases (HDACs) enzymes provided crucial role in transcriptional regulation of cells through deacetylation of nuclear histone proteins. Discoveries related to the HDAC8 enzyme activity signified the importance of HDAC8 isoform in cell proliferation, tumorigenesis, cancer, neuronal disorders, parasitic/viral infections and other epigenetic regulations. The pan-HDAC inhibitors can confront these conditions but have chances to affect epigenetic functions of other HDAC isoforms. Designing of selective HDAC8 inhibitors is a key feature to combat the pathophysiological and diseased conditions involving the HDAC8 activity. This review is concerned about the structural and positional aspects of HDAC8 in the HDAC family. It also covers the contributions of HDAC8 in the pathophysiological conditions, a preliminary discussion about the recent scenario of HDAC8 inhibitors. This review might help to deliver the structural, functional and computational information in order to identify and design potent and selective HDAC8 inhibitors for target specific treatment of diseases involving HDAC8 enzymatic activity.
|
Inhibition of recombinant full length human HDAC1 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
0.62
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC2 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
2.16
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC4 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
4.61
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC5 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
5.95
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC7 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
4.04
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC9 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
6.7
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC10 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
1.96
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of human HDAC1 expressed in baculovirus infected sf9 cells using p53 residues 379-382 (RHKKAc) as substrate by fluorescence-based assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC2 expressed in baculovirus infected sf9 cells using p53 residues 379-382 (RHKKAc) as substrate by fluorescence-based assay
|
Homo sapiens
|
0.3
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC3/NcoR2 expressed in sf9 cells using p53 residues 379-382 (RHKKAc) as substrate by fluorescence-based assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC8 expressed in baculovirus infected sf9 cells using p53 residues 379-382 (RHKAcKAc) as substrate by fluorescence-based assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC4 expressed in baculovirus infected sf9 cells using (Boc-Lys(trifluoroacetyl)-AMC) as substrate by fluorescence-based assay
|
Homo sapiens
|
0.6
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC5 expressed in baculovirus infected sf9 cells using (Boc-Lys(trifluoroacetyl)-AMC) as substrate by fluorescence-based assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC7 expressed in baculovirus infected sf9 cells using (Boc-Lys(trifluoroacetyl)-AMC) as substrate by fluorescence-based assay
|
Homo sapiens
|
119.0
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC9 expressed in baculovirus infected sf9 cells using (Boc-Lys(trifluoroacetyl)-AMC) as substrate by fluorescence-based assay
|
Homo sapiens
|
32.0
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC6 expressed in baculovirus infected sf9 cells using p53 residues 379-382 (RHKKAc) as substrate by fluorescence-based assay
|
Homo sapiens
|
77.0
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of HDAC10 (unknown origin)
|
Homo sapiens
|
0.5
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC11 expressed in baculovirus infected sf9 cells using (Boc-Lys(trifluoroacetyl)-AMC) as substrate by fluorescence-based assay
|
Homo sapiens
|
0.4
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of recombinant full length C-terminal FLAG His-tagged human HDAC1 expressed in baculovirus infected Sf21 insect cells using RHK-K(Ac)-AMC as substrate measured after 60 mins by fluorimetry analysis
|
Homo sapiens
|
0.11
nM
|
|
|
Inhibition of recombinant full length C-terminal GST fusion-tagged human HDAC2 expressed in baculovirus infected insect cells using RHK-K(Ac)-AMC as substrate measured after 60 mins by fluorimetry analysis
|
Homo sapiens
|
0.33
nM
|
|
|
Inhibition of C-terminal His-tagged recombinant human HDAC3 (1 to 428 residues)/N-terminal GST-tagged recombinant human NCoR2 (395 to 489 residues) co-expressed in baculovirus infected Sf9 cells using RHK-K(Ac)-AMCas substrate measured after 60 mins by fluorimetry analysis
|
Homo sapiens
|
4.86
nM
|
|
|
Inhibition of recombinant full length N-terminal GST fusion-tagged human HDAC6 expressed in baculovirus infected Sf9 insect cells using RHK-K(Ac)-AMC as substrate measured after 90 mins by fluorimetry analysis
|
Homo sapiens
|
76.8
nM
|
|
|
Antimalarial activity against asexual blood stage quinine-resistant Plasmodium falcipuram C2A assessed as parasite growth inhibition incubated for 72 hrs by SYBR Green I staining based fluorescence analysis
|
Plasmodium falciparum
|
2.52
nM
|
|
|
Antimalarial activity against asexual blood stage wild-type Plasmodium falciparum 3D7 assessed as parasite growth inhibition incubated for 72 hrs by SYBR Green I staining based fluorescence analysis
|
Plasmodium falciparum
|
4.01
nM
|
|
|
Antimalarial activity against asexual blood stage chloroquine-resistant Plasmodium falciparum Dd2 assessed as parasite growth inhibition incubated for 72 hrs by SYBR Green I staining based fluorescence analysis
|
Plasmodium falciparum
|
7.09
nM
|
|
|
Cytotoxicity against human HepG2 cells incubated for 72 hrs by CCK-8 assay
|
Homo sapiens
|
30.0
nM
|
|
|
Cytotoxicity against HEK293T cells incubated for 72 hrs by CCK-8 assay
|
Homo sapiens
|
60.0
nM
|
|
|
Antimalarial activity against asexual blood stage chloroquine-resistant Plasmodium falcipuram GB4 assessed as parasite growth inhibition incubated for 72 hrs by SYBR Green I staining based fluorescence analysis
|
Plasmodium falciparum
|
1.75
nM
|
|
|
Antimalarial activity against asexual blood stage sulfadoxine-pyrimethamine/mefloquine-resistant Plasmodium falcipuram CP286 assessed as parasite growth inhibition incubated for 72 hrs by SYBR Green I staining based fluorescence analysis
|
Plasmodium falciparum
|
2.04
nM
|
|
|
In vivo inhibition of C-terminal glmS fused HDAC1 in Plasmodium falcipuram 3D7 assessed as inhibition of parasite growth incubated for 4 hrs followed by compound washout and replacement with fresh medium with compounds measured after 68 hrs by SYBR Green I staining based fluorescence analysis
|
Plasmodium falciparum
|
5.59
nM
|
|
|
In vivo inhibition of C-terminal TY1 fused HDAC1 in Plasmodium falcipuram 3D7 assessed as inhibition of parasite growth incubated for 4 hrs followed by compound washout and replacement with fresh medium with compounds measured after 68 hrs by SYBR Green I staining based fluorescence analysis
|
Plasmodium falciparum
|
19.15
nM
|
|
|
Inhibition of recombinant human full length C-terminal His tagged HDAC2 (1 to 488 residues) expressed in baculovirus-infected Sf9 insect cells using Ac-peptide as substrate incubated for 4 hrs
|
Homo sapiens
|
1.1
nM
|
|
|
Inhibition of recombinant human full length C-terminal His/FLAG tagged HDAC1 (1 to 482 residues) expressed in baculovirus-infected Sf9 cells using Ac-peptide as substrate incubated for 4 hrs
|
Homo sapiens
|
0.46
nM
|
|
|
Inhibition of human C-terminal His tagged HDAC3 (1 to 428 residues) expressed in baculovirus-infected Sf9 cells using Ac-peptide as substrate incubated for 4 hrs
|
Homo sapiens
|
2.1
nM
|
|
|
Inhibition of recombinant human full length N-terminal GST tagged HDAC6 (1 to 1215 residues) expressed in baculovirus-infected Sf9 cells using Ac-peptide as substrate incubated for 4 hrs
|
Homo sapiens
|
34.9
nM
|
|
|
Inhibition of recombinant human full length C-terminal His-tagged HDAC8 expressed in baculovirus-infected Sf9 insect cells using Ac-peptide as substrate incubated for 4 hrs followed by trypsin addition and further incubated for 2 hrs
|
Homo sapiens
|
9.2
nM
|
|
