|
Inhibition of HDAC1
|
None
|
820.0
nM
|
|
Journal : J. Med. Chem.
Title : Histone deacetylase inhibitors: from bench to clinic.
Year : 2008
Volume : 51
Issue : 6
First Page : 1505
Last Page : 1529
Authors : Paris M, Porcelloni M, Binaschi M, Fattori D.
|
Inhibition of HDAC3
|
None
|
620.0
nM
|
|
Journal : J. Med. Chem.
Title : Histone deacetylase inhibitors: from bench to clinic.
Year : 2008
Volume : 51
Issue : 6
First Page : 1505
Last Page : 1529
Authors : Paris M, Porcelloni M, Binaschi M, Fattori D.
|
Inhibition of HDAC1 in HEK293 cells
|
None
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases.
Year : 2008
Volume : 18
Issue : 6
First Page : 1814
Last Page : 1819
Authors : Jones P, Altamura S, De Francesco R, Gallinari P, Lahm A, Neddermann P, Rowley M, Serafini S, Steinkühler C.
Abstract : It has been widely debated whether class IIa HDACs have catalytic deacetylase activity, and whether this plays any part in controlling gene expression. Herein, it has been demonstrated that class IIa HDACs isolated from mammalian cells are contaminated with other deacetylases, but can be prepared cleanly in Escherichia coli. These bacteria preparations have weak but measurable deacetylase activity. The low efficiency can be restored either by: mutation of an active site histidine to tyrosine, or by the use of a non-acetylated lysine substrate, allowing the development of assays to identify class IIa HDAC inhibitors.
|
Inhibition of HDAC3 in HEK293 cells
|
None
|
610.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases.
Year : 2008
Volume : 18
Issue : 6
First Page : 1814
Last Page : 1819
Authors : Jones P, Altamura S, De Francesco R, Gallinari P, Lahm A, Neddermann P, Rowley M, Serafini S, Steinkühler C.
Abstract : It has been widely debated whether class IIa HDACs have catalytic deacetylase activity, and whether this plays any part in controlling gene expression. Herein, it has been demonstrated that class IIa HDACs isolated from mammalian cells are contaminated with other deacetylases, but can be prepared cleanly in Escherichia coli. These bacteria preparations have weak but measurable deacetylase activity. The low efficiency can be restored either by: mutation of an active site histidine to tyrosine, or by the use of a non-acetylated lysine substrate, allowing the development of assays to identify class IIa HDAC inhibitors.
|
Inhibition of HDAC6 in HEK293 cells at 2 uM
|
None
|
32.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases.
Year : 2008
Volume : 18
Issue : 6
First Page : 1814
Last Page : 1819
Authors : Jones P, Altamura S, De Francesco R, Gallinari P, Lahm A, Neddermann P, Rowley M, Serafini S, Steinkühler C.
Abstract : It has been widely debated whether class IIa HDACs have catalytic deacetylase activity, and whether this plays any part in controlling gene expression. Herein, it has been demonstrated that class IIa HDACs isolated from mammalian cells are contaminated with other deacetylases, but can be prepared cleanly in Escherichia coli. These bacteria preparations have weak but measurable deacetylase activity. The low efficiency can be restored either by: mutation of an active site histidine to tyrosine, or by the use of a non-acetylated lysine substrate, allowing the development of assays to identify class IIa HDAC inhibitors.
|
Inhibition of human recombinant HDAC1 homogeneous fluorescence release assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
Year : 2008
Volume : 51
Issue : 14
First Page : 4072
Last Page : 4075
Authors : Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F, Paquin I, Bernstein N, Bouchain G, Vaisburg A, Jin Z, Gillespie J, Wang J, Fournel M, Yan PT, Trachy-Bourget MC, Kalita A, Lu A, Rahil J, MacLeod AR, Li Z, Besterman JM, Delorme D.
Abstract : The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
|
Inhibition of human recombinant HDAC2 homogeneous fluorescence release assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
Year : 2008
Volume : 51
Issue : 14
First Page : 4072
Last Page : 4075
Authors : Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F, Paquin I, Bernstein N, Bouchain G, Vaisburg A, Jin Z, Gillespie J, Wang J, Fournel M, Yan PT, Trachy-Bourget MC, Kalita A, Lu A, Rahil J, MacLeod AR, Li Z, Besterman JM, Delorme D.
Abstract : The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
|
Inhibition of human recombinant HDAC11 homogeneous fluorescence release assay
|
Homo sapiens
|
590.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
Year : 2008
Volume : 51
Issue : 14
First Page : 4072
Last Page : 4075
Authors : Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F, Paquin I, Bernstein N, Bouchain G, Vaisburg A, Jin Z, Gillespie J, Wang J, Fournel M, Yan PT, Trachy-Bourget MC, Kalita A, Lu A, Rahil J, MacLeod AR, Li Z, Besterman JM, Delorme D.
Abstract : The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
|
Antiproliferative activity against human HCT116 cells after 72 hrs by MTT assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
Year : 2008
Volume : 51
Issue : 14
First Page : 4072
Last Page : 4075
Authors : Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F, Paquin I, Bernstein N, Bouchain G, Vaisburg A, Jin Z, Gillespie J, Wang J, Fournel M, Yan PT, Trachy-Bourget MC, Kalita A, Lu A, Rahil J, MacLeod AR, Li Z, Besterman JM, Delorme D.
Abstract : The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
|
Antiproliferative activity against human A549 cells after 72 hrs by MTT assay
|
Homo sapiens
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
Year : 2008
Volume : 51
Issue : 14
First Page : 4072
Last Page : 4075
Authors : Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F, Paquin I, Bernstein N, Bouchain G, Vaisburg A, Jin Z, Gillespie J, Wang J, Fournel M, Yan PT, Trachy-Bourget MC, Kalita A, Lu A, Rahil J, MacLeod AR, Li Z, Besterman JM, Delorme D.
Abstract : The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
|
Antiproliferative activity against human Du145 cells after 72 hrs by MTT assay
|
Homo sapiens
|
670.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
Year : 2008
Volume : 51
Issue : 14
First Page : 4072
Last Page : 4075
Authors : Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F, Paquin I, Bernstein N, Bouchain G, Vaisburg A, Jin Z, Gillespie J, Wang J, Fournel M, Yan PT, Trachy-Bourget MC, Kalita A, Lu A, Rahil J, MacLeod AR, Li Z, Besterman JM, Delorme D.
Abstract : The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
|
Induction of p21cip/waf1 protein expression in human HCT116 cells relative to MS275
|
Homo sapiens
|
450.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide (MGCD0103), an orally active histone deacetylase inhibitor.
Year : 2008
Volume : 51
Issue : 14
First Page : 4072
Last Page : 4075
Authors : Zhou N, Moradei O, Raeppel S, Leit S, Frechette S, Gaudette F, Paquin I, Bernstein N, Bouchain G, Vaisburg A, Jin Z, Gillespie J, Wang J, Fournel M, Yan PT, Trachy-Bourget MC, Kalita A, Lu A, Rahil J, MacLeod AR, Li Z, Besterman JM, Delorme D.
Abstract : The design, synthesis, and biological evaluation of N-(2-aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino)methyl]benzamide 8 (MGCD0103) is described. Compound 8 is an isotype-selective small molecule histone deacetylase (HDAC) inhibitor that selectively inhibits HDACs 1-3 and 11 at submicromolar concentrations in vitro. 8 blocks cancer cell proliferation and induces histone acetylation, p21 (cip/waf1) protein expression, cell-cycle arrest, and apoptosis. 8 is orally bioavailable, has significant antitumor activity in vivo, has entered clinical trials, and shows promise as an anticancer drug.
|
Inhibition of human recombinant HDAC1
|
Homo sapiens
|
150.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).
Year : 2009
Volume : 19
Issue : 3
First Page : 644
Last Page : 649
Authors : Raeppel S, Zhou N, Gaudette F, Leit S, Paquin I, Larouche G, Moradei O, Fréchette S, Isakovic L, Delorme D, Fournel M, Kalita A, Lu A, Trachy-Bourget MC, Yan PT, Liu J, Rahil J, Wang J, Besterman JM, Murakami K, Li Z, Vaisburg A.
Abstract : Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
|
Antiproliferative activity against human HCT116 cells by MTT assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).
Year : 2009
Volume : 19
Issue : 3
First Page : 644
Last Page : 649
Authors : Raeppel S, Zhou N, Gaudette F, Leit S, Paquin I, Larouche G, Moradei O, Fréchette S, Isakovic L, Delorme D, Fournel M, Kalita A, Lu A, Trachy-Bourget MC, Yan PT, Liu J, Rahil J, Wang J, Besterman JM, Murakami K, Li Z, Vaisburg A.
Abstract : Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
|
Induction of p21WAF1/CIP1 expression in human HCT116 cells assessed as tubulin level after 16 hrs by luciferase assay
|
Homo sapiens
|
600.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).
Year : 2009
Volume : 19
Issue : 3
First Page : 644
Last Page : 649
Authors : Raeppel S, Zhou N, Gaudette F, Leit S, Paquin I, Larouche G, Moradei O, Fréchette S, Isakovic L, Delorme D, Fournel M, Kalita A, Lu A, Trachy-Bourget MC, Yan PT, Liu J, Rahil J, Wang J, Besterman JM, Murakami K, Li Z, Vaisburg A.
Abstract : Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
|
Inhibition of HDAC2
|
None
|
290.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : SAR and biological evaluation of analogues of a small molecule histone deacetylase inhibitor N-(2-aminophenyl)-4-((4-(pyridin-3-yl)pyrimidin-2-ylamino)methyl)benzamide (MGCD0103).
Year : 2009
Volume : 19
Issue : 3
First Page : 644
Last Page : 649
Authors : Raeppel S, Zhou N, Gaudette F, Leit S, Paquin I, Larouche G, Moradei O, Fréchette S, Isakovic L, Delorme D, Fournel M, Kalita A, Lu A, Trachy-Bourget MC, Yan PT, Liu J, Rahil J, Wang J, Besterman JM, Murakami K, Li Z, Vaisburg A.
Abstract : Analogues of the clinical compound MGCD0103 (A) were designed and synthesized. These compounds inhibit recombinant human HDAC1 with IC(50) values in the sub-micromolar range. In human cancer cells growing in culture these compounds induce hyperacetylation of histones, cause expression of the tumor suppressor protein p21(WAF1/CIP1), and inhibit cellular proliferation. Lead molecule of the series, compound 25 is metabolically stable, possesses favorable pharmacokinetic characteristics and is orally active in vivo in different mouse tumor xenograft models.
|
Inhibition of HDAC1 in human 293T cells after 16 hrs by fluorimetry relative to SAHA
|
Homo sapiens
|
80.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Sulfamides as novel histone deacetylase inhibitors.
Year : 2009
Volume : 19
Issue : 2
First Page : 336
Last Page : 340
Authors : Wahhab A, Smil D, Ajamian A, Allan M, Chantigny Y, Therrien E, Nguyen N, Manku S, Leit S, Rahil J, Petschner AJ, Lu AH, Nicolescu A, Lefebvre S, Montcalm S, Fournel M, Yan TP, Li Z, Besterman JM, Déziel R.
Abstract : The sulfamide moiety has been utilized to design novel HDAC inhibitors. The potency and selectivity of these inhibitors were influenced both by the nature of the scaffold, and the capping group. Linear long-chain-based analogs were primarily HDAC6-selective, while analogs based on the lysine scaffold resulted in potent HDAC1 and HDAC6 inhibitors.
|
Inhibition of recombinant C-terminal FLAG-tagged HDAC1 expressed in baculovirus after 10 mins by fluorimetric analysis
|
None
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors.
Year : 2009
Volume : 19
Issue : 19
First Page : 5684
Last Page : 5688
Authors : Tessier P, Smil DV, Wahhab A, Leit S, Rahil J, Li Z, Déziel R, Besterman JM.
Abstract : We have identified a series of diphenylmethylene hydroxamic acids as novel and selective HDAC class IIa inhibitors. The original hit, N-hydroxy-2,2-diphenylacetamide (6), has sub-micromolar class IIa HDAC inhibitory activity, while the rigidified oxygen analogue, N-hydroxy-9H-xanthene-9-carboxamide (13), is slightly more selective for HDAC7 with an IC(50) of 0.05muM. Substitution of 6 allows for the modulation of selectivity and potency amongst the class IIa HDAC isotypes.
|
Inhibition of recombinant C-terminal FLAG-tagged HDAC2 expressed in baculovirus after 10 mins by fluorimetric analysis
|
None
|
180.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Diphenylmethylene hydroxamic acids as selective class IIa histone deacetylase inhibitors.
Year : 2009
Volume : 19
Issue : 19
First Page : 5684
Last Page : 5688
Authors : Tessier P, Smil DV, Wahhab A, Leit S, Rahil J, Li Z, Déziel R, Besterman JM.
Abstract : We have identified a series of diphenylmethylene hydroxamic acids as novel and selective HDAC class IIa inhibitors. The original hit, N-hydroxy-2,2-diphenylacetamide (6), has sub-micromolar class IIa HDAC inhibitory activity, while the rigidified oxygen analogue, N-hydroxy-9H-xanthene-9-carboxamide (13), is slightly more selective for HDAC7 with an IC(50) of 0.05muM. Substitution of 6 allows for the modulation of selectivity and potency amongst the class IIa HDAC isotypes.
|
Inhibition of human HDAC1
|
Homo sapiens
|
9.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical phylogenetics of histone deacetylases.
Year : 2010
Volume : 6
Issue : 3
First Page : 238
Last Page : 243
Authors : Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R.
Abstract : The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as nonselective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of, to our knowledge, the first nonselective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.
|
Inhibition of human HDAC2
|
Homo sapiens
|
32.4
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical phylogenetics of histone deacetylases.
Year : 2010
Volume : 6
Issue : 3
First Page : 238
Last Page : 243
Authors : Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R.
Abstract : The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as nonselective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of, to our knowledge, the first nonselective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.
|
Inhibition of human HDAC3
|
Homo sapiens
|
265.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Chemical phylogenetics of histone deacetylases.
Year : 2010
Volume : 6
Issue : 3
First Page : 238
Last Page : 243
Authors : Bradner JE, West N, Grachan ML, Greenberg EF, Haggarty SJ, Warnow T, Mazitschek R.
Abstract : The broad study of histone deacetylases in chemistry, biology and medicine relies on tool compounds to derive mechanistic insights. A phylogenetic analysis of class I and II histone deacetylases (HDACs) as targets of a comprehensive, structurally diverse panel of inhibitors revealed unexpected isoform selectivity even among compounds widely perceived as nonselective. The synthesis and study of a focused library of cinnamic hydroxamates allowed the identification of, to our knowledge, the first nonselective HDAC inhibitor. These data will guide a more informed use of HDAC inhibitors as chemical probes and therapeutic agents.
|
Inhibition of purified recombinant HDAC1
|
None
|
152.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The design, synthesis and structure-activity relationships of novel isoindoline-based histone deacetylase inhibitors.
Year : 2011
Volume : 21
Issue : 16
First Page : 4909
Last Page : 4912
Authors : Shultz M, Fan J, Chen C, Cho YS, Davis N, Bickford S, Buteau K, Cao X, Holmqvist M, Hsu M, Jiang L, Liu G, Lu Q, Patel C, Suresh JR, Selvaraj M, Urban L, Wang P, Yan-Neale Y, Whitehead L, Zhang H, Zhou L, Atadja P.
Abstract : The design, synthesis and biological evaluation of a novel series of isoindoline-based hydroxamates is described. Several analogs were shown to inhibit HDAC1 with IC(50) values in the low nanomolar range and inhibit cellular proliferation of HCT116 human colon cancer cells in the sub-micromolar range. The cellular potency of compound 17e was found to have greater in vitro anti-proliferative activity than several compounds in late stage clinical trials for the treatment of cancer. The in vitro safety profiles of selected compounds were assessed and shown to be suitable for further lead optimization.
|
Antiproliferative activity against human HCT116 cells
|
Homo sapiens
|
310.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The design, synthesis and structure-activity relationships of novel isoindoline-based histone deacetylase inhibitors.
Year : 2011
Volume : 21
Issue : 16
First Page : 4909
Last Page : 4912
Authors : Shultz M, Fan J, Chen C, Cho YS, Davis N, Bickford S, Buteau K, Cao X, Holmqvist M, Hsu M, Jiang L, Liu G, Lu Q, Patel C, Suresh JR, Selvaraj M, Urban L, Wang P, Yan-Neale Y, Whitehead L, Zhang H, Zhou L, Atadja P.
Abstract : The design, synthesis and biological evaluation of a novel series of isoindoline-based hydroxamates is described. Several analogs were shown to inhibit HDAC1 with IC(50) values in the low nanomolar range and inhibit cellular proliferation of HCT116 human colon cancer cells in the sub-micromolar range. The cellular potency of compound 17e was found to have greater in vitro anti-proliferative activity than several compounds in late stage clinical trials for the treatment of cancer. The in vitro safety profiles of selected compounds were assessed and shown to be suitable for further lead optimization.
|
Inhibition of CYP3A4
|
None
|
570.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The design, synthesis and structure-activity relationships of novel isoindoline-based histone deacetylase inhibitors.
Year : 2011
Volume : 21
Issue : 16
First Page : 4909
Last Page : 4912
Authors : Shultz M, Fan J, Chen C, Cho YS, Davis N, Bickford S, Buteau K, Cao X, Holmqvist M, Hsu M, Jiang L, Liu G, Lu Q, Patel C, Suresh JR, Selvaraj M, Urban L, Wang P, Yan-Neale Y, Whitehead L, Zhang H, Zhou L, Atadja P.
Abstract : The design, synthesis and biological evaluation of a novel series of isoindoline-based hydroxamates is described. Several analogs were shown to inhibit HDAC1 with IC(50) values in the low nanomolar range and inhibit cellular proliferation of HCT116 human colon cancer cells in the sub-micromolar range. The cellular potency of compound 17e was found to have greater in vitro anti-proliferative activity than several compounds in late stage clinical trials for the treatment of cancer. The in vitro safety profiles of selected compounds were assessed and shown to be suitable for further lead optimization.
|
Antiproliferative activity against human HCT116 cells assessed as growth inhibition
|
Homo sapiens
|
310.0
nM
|
|
Journal : J. Med. Chem.
Title : Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors.
Year : 2011
Volume : 54
Issue : 13
First Page : 4752
Last Page : 4772
Authors : Shultz MD, Cao X, Chen CH, Cho YS, Davis NR, Eckman J, Fan J, Fekete A, Firestone B, Flynn J, Green J, Growney JD, Holmqvist M, Hsu M, Jansson D, Jiang L, Kwon P, Liu G, Lombardo F, Lu Q, Majumdar D, Meta C, Perez L, Pu M, Ramsey T, Remiszewski S, Skolnik S, Traebert M, Urban L, Uttamsingh V, Wang P, Whitebread S, Whitehead L, Yan-Neale Y, Yao YM, Zhou L, Atadja P.
Abstract : Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.
|
Inhibition of human ERG at 30 uM
|
Homo sapiens
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors.
Year : 2011
Volume : 54
Issue : 13
First Page : 4752
Last Page : 4772
Authors : Shultz MD, Cao X, Chen CH, Cho YS, Davis NR, Eckman J, Fan J, Fekete A, Firestone B, Flynn J, Green J, Growney JD, Holmqvist M, Hsu M, Jansson D, Jiang L, Kwon P, Liu G, Lombardo F, Lu Q, Majumdar D, Meta C, Perez L, Pu M, Ramsey T, Remiszewski S, Skolnik S, Traebert M, Urban L, Uttamsingh V, Wang P, Whitebread S, Whitehead L, Yan-Neale Y, Yao YM, Zhou L, Atadja P.
Abstract : Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.
|
Inhibition of human recombinant HDAC1 expressed in Sf9 cells incubated for 2 hrs using RHKK-Ac fluorogenic substrate
|
Homo sapiens
|
102.0
nM
|
|
Journal : J. Med. Chem.
Title : Selective histone deacetylase 6 inhibitors bearing substituted urea linkers inhibit melanoma cell growth.
Year : 2012
Volume : 55
Issue : 22
First Page : 9891
Last Page : 9899
Authors : Bergman JA, Woan K, Perez-Villarroel P, Villagra A, Sotomayor EM, Kozikowski AP.
Abstract : The incidence of malignant melanoma has dramatically increased in recent years thus requiring the need for improved therapeutic strategies. In our efforts to design selective histone deactylase inhibitors (HDACI), we discovered that the aryl urea 1 is a modestly potent yet nonselective inhibitor. Structure-activity relationship studies revealed that adding substituents to the nitrogen atom of the urea so as to generate compounds bearing a branched linker group results in increased potency and selectivity for HDAC6. Compound 5 g shows low nanomolar inhibitory potency against HDAC6 and a selectivity of ∼600-fold relative to the inhibition of HDAC1. These HDACIs were evaluated for their ability to inhibit the growth of B16 melanoma cells with the most potent and selective HDAC6I being found to decrease tumor cell growth. To the best of our knowledge, this work constitutes the first report of HDAC6-selective inhibitors that possess antiproliferative effects against melanoma cells.
|
Cytotoxicity against human HCT116 cells after 72 hrs by MTT assay
|
Homo sapiens
|
327.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and bioevalution of novel benzamides derivatives as HDAC inhibitors.
Year : 2013
Volume : 23
Issue : 1
First Page : 179
Last Page : 182
Authors : Li Y, Zhou Y, Qian P, Wang Y, Jiang F, Yao Z, Hu W, Zhao Y, Li S.
Abstract : A series of novel benzamides derivatives was designed and synthesized as HDAC inhibitors. Exploration of the structure-activity relationships resulted in compounds that are potent in vitro. In addition, the best compound 1a exhibited an acceptable pharmacokinetic profile with bioavailability in rat of 81% and could be considered as a candidate compound for further development.
|
Inhibition of HDAC1 (unknown origin)
|
Homo sapiens
|
184.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and bioevalution of novel benzamides derivatives as HDAC inhibitors.
Year : 2013
Volume : 23
Issue : 1
First Page : 179
Last Page : 182
Authors : Li Y, Zhou Y, Qian P, Wang Y, Jiang F, Yao Z, Hu W, Zhao Y, Li S.
Abstract : A series of novel benzamides derivatives was designed and synthesized as HDAC inhibitors. Exploration of the structure-activity relationships resulted in compounds that are potent in vitro. In addition, the best compound 1a exhibited an acceptable pharmacokinetic profile with bioavailability in rat of 81% and could be considered as a candidate compound for further development.
|
Cytotoxicity against human HCT116 cells assessed as growth inhibition by measuring cellular ATP level after 72 hrs by cell-titer glo assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit.
Year : 2013
Volume : 56
Issue : 15
First Page : 6156
Last Page : 6174
Authors : Marson CM, Matthews CJ, Yiannaki E, Atkinson SJ, Soden PE, Shukla L, Lamadema N, Thomas NS.
Abstract : The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.
|
Inhibition of recombinant C-terminal FLAG-tagged HDAC1 (unknown origin) expressed in Escherichia coli BL21 using MAL as substrate incubated for 1 hr prior to substrate addition measured after 60 mins by fluorescence plate reader analysis
|
Homo sapiens
|
98.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit.
Year : 2013
Volume : 56
Issue : 15
First Page : 6156
Last Page : 6174
Authors : Marson CM, Matthews CJ, Yiannaki E, Atkinson SJ, Soden PE, Shukla L, Lamadema N, Thomas NS.
Abstract : The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.
|
Inhibition of recombinant HDAC3-NCoR1 (unknown origin) using MAL as substrate incubated for 3 hrs prior to substrate addition measured after 60 mins by fluorescence plate reader analysis
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit.
Year : 2013
Volume : 56
Issue : 15
First Page : 6156
Last Page : 6174
Authors : Marson CM, Matthews CJ, Yiannaki E, Atkinson SJ, Soden PE, Shukla L, Lamadema N, Thomas NS.
Abstract : The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.
|
Inhibition of recombinant His-tagged HDAC2 (1 to 488) (unknown origin) using MAL as substrate incubated for 3 hrs prior to substrate addition measured after 60 mins by fluorescence plate reader analysis
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit.
Year : 2013
Volume : 56
Issue : 15
First Page : 6156
Last Page : 6174
Authors : Marson CM, Matthews CJ, Yiannaki E, Atkinson SJ, Soden PE, Shukla L, Lamadema N, Thomas NS.
Abstract : The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide 24a gave respective IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by 24a was observed, with respective IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.
|
Inhibition of HDAC2 (unknown origin)
|
Homo sapiens
|
280.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The discovery and optimization of novel dual inhibitors of topoisomerase II and histone deacetylase.
Year : 2013
Volume : 21
Issue : 22
First Page : 6981
Last Page : 6995
Authors : Zhang X, Bao B, Yu X, Tong L, Luo Y, Huang Q, Su M, Sheng L, Li J, Zhu H, Yang B, Zhang X, Chen Y, Lu W.
Abstract : A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24 d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity.
|
Inhibition of human recombinant HDAC1 expressed in baculovirus infected insect high5 cells using Ac-Lys-Tyr-Lys (epsilon-acetyl)-AMC as substrate after 3 to 24 hrs by fluorescence assay
|
Homo sapiens
|
950.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The discovery and optimization of novel dual inhibitors of topoisomerase II and histone deacetylase.
Year : 2013
Volume : 21
Issue : 22
First Page : 6981
Last Page : 6995
Authors : Zhang X, Bao B, Yu X, Tong L, Luo Y, Huang Q, Su M, Sheng L, Li J, Zhu H, Yang B, Zhang X, Chen Y, Lu W.
Abstract : A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24 d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity.
|
Inhibition of recombinant human HDAC1 expressed in baculovirus infected insect High5 cells using Ac-Lys-Tyr-Lys (epsilon-acetyl)-AMC as substrate after 24 hrs by fluorescence assay
|
Homo sapiens
|
390.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Inhibition of recombinant human HDAC2 expressed in baculovirus infected insect High5 cells using Ac-Lys-Tyr-Lys (epsilon-acetyl)-AMC as substrate after 24 hrs by fluorescence assay
|
Homo sapiens
|
170.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Inhibition of recombinant human HDAC3 expressed in baculovirus infected insect High5 cells using Ac-Lys-Tyr-Lys (epsilon-acetyl)-AMC as substrate after 3 hrs by fluorescence assay
|
Homo sapiens
|
360.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Cytotoxicity against human HCT116 cells assessed as growth inhibition after 72 hrs by MTT assay
|
Homo sapiens
|
396.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Cytotoxicity against human SW620 cells assessed as growth inhibition after 72 hrs by MTT assay
|
Homo sapiens
|
419.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Cytotoxicity against human Hep3B cells assessed as growth inhibition after 72 hrs by MTT assay
|
Homo sapiens
|
823.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Cytotoxicity against human HepG2 cells assessed as growth inhibition after 72 hrs by MTT assay
|
Homo sapiens
|
876.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Cytotoxicity against human SNU16 cells assessed as growth inhibition after 72 hrs by MTT assay
|
Homo sapiens
|
142.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Cytotoxicity against human MKN45 cells assessed as growth inhibition after 72 hrs by MTT assay
|
Homo sapiens
|
610.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors.
Year : 2015
Volume : 95
First Page : 127
Last Page : 135
Authors : Zhang X, Kong Y, Zhang J, Su M, Zhou Y, Zang Y, Li J, Chen Y, Fang Y, Zhang X, Lu W.
Abstract : A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).
|
Inhibition of C-flagged recombinant HDAC1 (unknown origin) pre-incubated for 1 hr before substrate addition by homogeneous fluorogenic HDAC assay
|
Homo sapiens
|
98.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit.
Year : 2015
Volume : 58
Issue : 17
First Page : 6803
Last Page : 6818
Authors : Marson CM, Matthews CJ, Atkinson SJ, Lamadema N, Thomas NS.
Abstract : A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.
|
Inhibition of His-tagged recombinant HDAC2 (1 to 488 residues) (unknown origin) pre-incubated for 3 hrs before substrate addition by homogeneous fluorogenic HDAC assay
|
Homo sapiens
|
22.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit.
Year : 2015
Volume : 58
Issue : 17
First Page : 6803
Last Page : 6818
Authors : Marson CM, Matthews CJ, Atkinson SJ, Lamadema N, Thomas NS.
Abstract : A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.
|
Inhibition of recombinant HDAC3/NCOR2 (unknown origin) pre-incubated for 3 hrs before substrate addition by homogeneous fluorogenic HDAC assay
|
Homo sapiens
|
45.0
nM
|
|
Journal : J. Med. Chem.
Title : Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit.
Year : 2015
Volume : 58
Issue : 17
First Page : 6803
Last Page : 6818
Authors : Marson CM, Matthews CJ, Atkinson SJ, Lamadema N, Thomas NS.
Abstract : A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.
|
Inhibition of His-flagged recombinant HDAC6 (unknown origin) at 20 uM pre-incubated for 1 hr before substrate addition by homogeneous fluorogenic HDAC assay
|
Homo sapiens
|
68.0
%
|
|
Journal : J. Med. Chem.
Title : Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding Unit.
Year : 2015
Volume : 58
Issue : 17
First Page : 6803
Last Page : 6818
Authors : Marson CM, Matthews CJ, Atkinson SJ, Lamadema N, Thomas NS.
Abstract : A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide 15k gave respective IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of 15k. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was observed for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.
|
Inhibition of HDAC1 (unknown origin) using Boc-Lys(acetyl)-AMC as substrate preincubated for 5 mins followed by substrate addition by fluorescence assay
|
Homo sapiens
|
171.0
nM
|
|
Journal : MedChemComm
Title : Navigating into the chemical space between MGCD0103 and SAHA: novel histone deacetylase inhibitors as a promising lead
Year : 2015
Volume : 6
Issue : 10
First Page : 1816
Last Page : 1825
Authors : Zhang X, Lv P, Li D, Zhang W, Zhu H
|
Inhibition of HDAC2 (unknown origin) using Boc-Lys(acetyl)-AMC as substrate preincubated for 5 mins followed by substrate addition by fluorescence assay
|
Homo sapiens
|
283.0
nM
|
|
Journal : MedChemComm
Title : Navigating into the chemical space between MGCD0103 and SAHA: novel histone deacetylase inhibitors as a promising lead
Year : 2015
Volume : 6
Issue : 10
First Page : 1816
Last Page : 1825
Authors : Zhang X, Lv P, Li D, Zhang W, Zhu H
|
Inhibition Assay: HDAC inhibition assays were performed by Reaction Biology Corp. (Malvern, Pa.) using isolated human, recombinant full-length HDAC1 and -6 from a baculovirus expression system in Sf9 cells. An acetylated fluorogenic peptide, RHKKAc, derived from residues 379-382 of p53 was used as substrate. The reaction buffer was made up of 50 mM Tris-HCl pH 8.0, 127 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, 1 mg/mL BSA, and a final concentration of 1% DMSO. Compounds were delivered in DMSO and delivered to enzyme mixture with preincubation of 5-10 min followed by substrate addition and incubation for 2 h at 30° C. Trichostatin A and developer were added to quench the reaction and generate fluorescence, respectively. Dose-response curves were generated starting at 30 μM compound with three-fold serial dilutions to generate a 10-dose plot.
|
Homo sapiens
|
102.0
nM
|
|
Title : Selective histone deactylase 6 inhibitors
Year : 2016
|
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 recombinant full length human C-terminal FLAG-tagged HDAC11 expressed in baculovirus infected Sf9 cells using Boc-Lys(epsilon-Ac)-AMC as substrate pretreated for 10 mins followed by substrate addition by fluorometric method
|
Homo sapiens
|
590.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Stabilizing HDAC11 with SAHA to assay slow-binding benzamide inhibitors.
Year : 2017
Volume : 27
Issue : 13
First Page : 2943
Last Page : 2945
Authors : Tian Y, Lv W, Li X, Wang C, Wang D, Wang PG, Jin J, Shen J.
Abstract : Among 18 human histone deacetylases (HDAC), HDAC11 is least studied. MS275, a benzamide HDAC inhibitor (HDACi), was stereotypically considered to selectively target Class I HDACs. We verified this slow-binding inhibitor also targeted HDAC11. In a traditional enzyme based assay, MS275 at low concentrations surprisingly behaved as an agonist. This was attributed to the poor stability of HDAC11 which lost 40% activity in 3h at 37°C. By adding 0.2μM SAHA, HDAC11 activity was stabilized during the 3-h assay period. Since 0.2μM SAHA inhibited 50% HDAC11 activity, the apparent IC50' of MS275 was adjusted to the true IC50=0.65μM. Finally, the new method demonstrated its superiority in one-dose-screening assays by decreasing false negative results. This work highlighted an optimized strategy to assay slow-binding inhibitors of unstable proteins with known fast-binding inhibitors. It should be especially useful in a hit-discovery stage to find moderate potent compounds.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-7.08
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
18.74
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
1.046
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
1.27
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
3.12
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
1.27
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
3.12
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of human C-terminal Flag-tagged HDAC1 expressed in sf9 cells using Boc-Lys(Ac)-AMC as substrate preincubated for 10 mins followed by substrate addition by fluorometry
|
Homo sapiens
|
200.0
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 C-terminal Flag-tagged HDAC2 expressed in sf9 cells using Boc-Lys(Ac)-AMC as substrate preincubated for 10 mins followed by substrate addition by fluorometry
|
Homo sapiens
|
300.0
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 C-terminal Flag-tagged HDAC11 expressed in sf9 cells using Boc-Lys(Ac)-AMC as substrate preincubated for 10 mins followed by substrate addition by fluorometry
|
Homo sapiens
|
600.0
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 HDAC1 (unknown origin) assessed as release of 7-amino-4-methylcoumarin incubated in room temperature for 15 min measured by Spectra max microtitre plate reader
|
Homo sapiens
|
68.2
nM
|
|
