|
Inhibition of human recombinant HDAC1
|
Homo sapiens
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC2
|
Homo sapiens
|
900.0
nM
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of HDAC in human HCT116 cells at 60 uM
|
Homo sapiens
|
81.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC1 at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC2 at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC3 at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC8 at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC4 at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC5 at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC6 at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of human recombinant HDAC7 at 20 uM
|
Homo sapiens
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.
Year : 2007
Volume : 50
Issue : 23
First Page : 5543
Last Page : 5546
Authors : Moradei OM, Mallais TC, Frechette S, Paquin I, Tessier PE, Leit SM, Fournel M, Bonfils C, Trachy-Bourget MC, Liu J, Yan TP, Lu AH, Rahil J, Wang J, Lefebvre S, Li Z, Vaisburg AF, Besterman JM.
Abstract : Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
|
Inhibition of HDAC1
|
None
|
570.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Exploration of the internal cavity of histone deacetylase (HDAC) with selective HDAC1/HDAC2 inhibitors (SHI-1:2).
Year : 2008
Volume : 18
Issue : 3
First Page : 973
Last Page : 978
Authors : Methot JL, Chakravarty PK, Chenard M, Close J, Cruz JC, Dahlberg WK, Fleming J, Hamblett CL, Hamill JE, Harrington P, Harsch A, Heidebrecht R, Hughes B, Jung J, Kenific CM, Kral AM, Meinke PT, Middleton RE, Ozerova N, Sloman DL, Stanton MG, Szewczak AA, Tyagarajan S, Witter DJ, Secrist JP, Miller TA.
Abstract : We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.
|
Antitumor activity against human HCT116 cells xenografted in mouse at 30 mg/kg
|
Homo sapiens
|
52.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Inside HDAC with HDAC inhibitors.
Year : 2010
Volume : 45
Issue : 6
First Page : 2095
Last Page : 2116
Authors : Bertrand P.
Abstract : Histone deacetylase inhibitors are a large group of diverse molecules intrinsically able to inhibit cell proliferation in various cancer cell lines. Their apoptotic effects have been linked to the modulation in the expression of several regulatory tumor suppressor genes caused by the modified status of histone acetylation, a key event in chromatin remodelling. As the initial histone deacetylase activity of HDAC has been extended to other proteins, the possible other biological mechanisms modified by HDAC inhibitor treatments are still to be clarified. The need for HDAC isoform selective inhibitors is an important issue to serve this goal. This review discusses the approaches proposed by several research groups working on the synthesis of HDAC inhibitors, based on modelling studies and the way these findings were used to obtain new HDAC inhibitors with possible isoform selectivity.
|
Inhibition of human HDAC1
|
Homo sapiens
|
50.0
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
|
190.0
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 HDAC3
|
Homo sapiens
|
550.0
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 HDAC in HeLa cells nuclear extract at 12.5 uM by fluorimetric assay
|
Homo sapiens
|
42.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cross metathesis with hydroxamate and benzamide BOC-protected alkenes to access HDAC inhibitors and their biological evaluation highlighted intrinsic activity of BOC-protected dihydroxamates.
Year : 2016
Volume : 26
Issue : 1
First Page : 154
Last Page : 159
Authors : Zwick V, Nurisso A, Simões-Pires C, Bouchet S, Martinet N, Lehotzky A, Ovadi J, Cuendet M, Blanquart C, Bertrand P.
Abstract : Conditions for the metathesis of alkenes in the convergent synthesis of HDAC inhibitors have been improved by continuous catalyst flow injection in the reaction media. Intermediate and target compounds obtained were tested for their ability to induce HDAC inhibition and tubulin acetylation, revealing the key role of the tert-butyloxycarbonyl (BOC) group for more HDAC6 selectivity. Molecular modelling added rationale for this BOC effect.
|
Inhibition of human recombinant HDAC1 (1 to 482 residues) expressed in Baculovirus using Ac-Leu-Gly-Lys(Ac)-AMC as substrate after 3 hrs by fluorescence assay
|
Homo sapiens
|
60.0
nM
|
|
Journal : J Med Chem
Title : Small Molecule Inhibitors Simultaneously Targeting Cancer Metabolism and Epigenetics: Discovery of Novel Nicotinamide Phosphoribosyltransferase (NAMPT) and Histone Deacetylase (HDAC) Dual Inhibitors.
Year : 2017
Volume : 60
Issue : 19
First Page : 7965
Last Page : 7983
Authors : Dong G, Chen W, Wang X, Yang X, Xu T, Wang P, Zhang W, Rao Y, Miao C, Sheng C.
Abstract : Cancer metabolism and epigenetics are among the most intensely pursued research areas in anticancer drug discovery. Here we report the first small molecules that simultaneously inhibit nicotinamide phosphoribosyltransferase (NAMPT) and histone deacetylase (HDAC), two important targets of cancer metabolism and epigenetics, respectively. Through iterative structure-based drug design, chemical synthesis, and biological assays, a highly potent dual NAMPT and HDAC inhibitor was successfully identified. Compound 35 possessed excellent and balanced activities against both NAMPT (IC50 = 31 nM) and HDAC1 (IC50 = 55 nM). It could effectively induce cell apoptosis and autophagy and ultimately led to cell death. Importantly, compound 35 showed excellent in vivo antitumor efficacy in the HCT116 xenograft model. This proof-of-concept study demonstrates the feasibility of discovering an inhibitor targeting cancer metabolism and epigenetics and provides an efficient strategy for multitarget antitumor drug discovery.
|
Inhibition of HDAC in human HeLa cell nuclear extract at 0.625 uM using Fluor de Lys green as substrate after 5 mins by fluorescence assay
|
Homo sapiens
|
32.5
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel hydroxamates and 2-aminobenzamides as potent histone deacetylase inhibitors and antitumor agents.
Year : 2017
Volume : 134
First Page : 1
Last Page : 12
Authors : Xie R, Yao Y, Tang P, Chen G, Liu X, Yun F, Cheng C, Wu X, Yuan Q.
Abstract : Many studies have indicated that histone deacetylase (HDAC) inhibitors are promising agents for the treatment of cancer. With the aim to search for novel potent HDAC inhibitors, we designed and synthesized two series of hydroxamates and 2-aminobenzamides compounds as HDAC inhibitors and antitumor agents. Those compounds were investigated for their HDAC enzymatic inhibitory activities and in vitro anti-proliferation activities against diverse cancer cell line (A549, HepG2, MGC80-3 and HCT116). Most of the synthesized compounds displayed potent HDAC inhibitory activity and antiproliferative activity. In particular, Compound 12a, N-(2-aminophenyl)-4-[(4-fluorophenoxy)methyl]benzamide, was shown to have the most HDAC inhibitory activity (70.6% inhibition at 5 μM) and antitumor activity with IC50 value of as low as 3.84 μM against HepG2 human liver hepatocellular carcinoma cell line, more than 4.8-fold lower than CS055 and 5.9-fold lower than CI994. HDAC isoform selectivity assay indicated 12a is a potent HDAC2 inhibitor. Docking study of 12a suggested that it bound tightly to the binding pocket of HDAC2. Further investigation showed that 12a could inhibit the migration and colony formation of A549 cancer cells. Furthermore, 12a remarkably induced apoptosis and G2/M phase cell cycle arrest in A549 cancer cells. Those results indicated that compound 12a could be a promising candidate for treatment of cancer.
|
Inhibition of HDAC in human HeLa cell nuclear extract at 5 uM using Fluor de Lys green as substrate after 5 mins by fluorescence assay
|
Homo sapiens
|
49.4
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel hydroxamates and 2-aminobenzamides as potent histone deacetylase inhibitors and antitumor agents.
Year : 2017
Volume : 134
First Page : 1
Last Page : 12
Authors : Xie R, Yao Y, Tang P, Chen G, Liu X, Yun F, Cheng C, Wu X, Yuan Q.
Abstract : Many studies have indicated that histone deacetylase (HDAC) inhibitors are promising agents for the treatment of cancer. With the aim to search for novel potent HDAC inhibitors, we designed and synthesized two series of hydroxamates and 2-aminobenzamides compounds as HDAC inhibitors and antitumor agents. Those compounds were investigated for their HDAC enzymatic inhibitory activities and in vitro anti-proliferation activities against diverse cancer cell line (A549, HepG2, MGC80-3 and HCT116). Most of the synthesized compounds displayed potent HDAC inhibitory activity and antiproliferative activity. In particular, Compound 12a, N-(2-aminophenyl)-4-[(4-fluorophenoxy)methyl]benzamide, was shown to have the most HDAC inhibitory activity (70.6% inhibition at 5 μM) and antitumor activity with IC50 value of as low as 3.84 μM against HepG2 human liver hepatocellular carcinoma cell line, more than 4.8-fold lower than CS055 and 5.9-fold lower than CI994. HDAC isoform selectivity assay indicated 12a is a potent HDAC2 inhibitor. Docking study of 12a suggested that it bound tightly to the binding pocket of HDAC2. Further investigation showed that 12a could inhibit the migration and colony formation of A549 cancer cells. Furthermore, 12a remarkably induced apoptosis and G2/M phase cell cycle arrest in A549 cancer cells. Those results indicated that compound 12a could be a promising candidate for treatment of cancer.
|
Inhibition of human HDAC1 expressed in 293T cells at 100 uM using Ac-KGLGK(Ac)-MCA as substrate measured after 30 mins by fluorescence assay relative to control
|
Homo sapiens
|
67.0
%
|
|
Journal : ACS Med Chem Lett
Title : Design, Synthesis, and Blood-Brain Barrier Transport Study of Pyrilamine Derivatives as Histone Deacetylase Inhibitors.
Year : 2018
Volume : 9
Issue : 9
First Page : 884
Last Page : 888
Authors : Hiranaka S, Tega Y, Higuchi K, Kurosawa T, Deguchi Y, Arata M, Ito A, Yoshida M, Nagaoka Y, Sumiyoshi T.
Abstract : We designed and synthesized a pyrilamine derivative 1 as a selective class I HDAC inhibitor that targets pyrilamine-sensitive proton-coupled organic cation antiporter (PYSOCA) at the blood-brain barrier (BBB). Introduction of pyrilamine moiety to benzamide type HDAC inhibitors kept selective class I HDAC inhibitory activity and increased BBB permeability. Our BBB transport study showed that compound 1 is a substrate of PYSOCA. Thus, our findings suggest that the hybrid method of HDAC inhibitor and substrate of PYSOCA such as pyrilamine is useful for development of HDAC inhibitors with increased BBB permeability.
|
Inhibition of mouse HDAC6 expressed in 293T cells at 100 uM using Ac-KGLGK(Ac)-MCA as substrate measured after 30 mins by fluorescence assay relative to control
|
Mus musculus
|
18.0
%
|
|
Journal : ACS Med Chem Lett
Title : Design, Synthesis, and Blood-Brain Barrier Transport Study of Pyrilamine Derivatives as Histone Deacetylase Inhibitors.
Year : 2018
Volume : 9
Issue : 9
First Page : 884
Last Page : 888
Authors : Hiranaka S, Tega Y, Higuchi K, Kurosawa T, Deguchi Y, Arata M, Ito A, Yoshida M, Nagaoka Y, Sumiyoshi T.
Abstract : We designed and synthesized a pyrilamine derivative 1 as a selective class I HDAC inhibitor that targets pyrilamine-sensitive proton-coupled organic cation antiporter (PYSOCA) at the blood-brain barrier (BBB). Introduction of pyrilamine moiety to benzamide type HDAC inhibitors kept selective class I HDAC inhibitory activity and increased BBB permeability. Our BBB transport study showed that compound 1 is a substrate of PYSOCA. Thus, our findings suggest that the hybrid method of HDAC inhibitor and substrate of PYSOCA such as pyrilamine is useful for development of HDAC inhibitors with increased BBB permeability.
|
Antiproliferative activity against human MGC803 cells at 2 uM after 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
9.5
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents.
Year : 2018
Volume : 143
First Page : 320
Last Page : 333
Authors : Xie R, Li Y, Tang P, Yuan Q.
Abstract : A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC50 values of as low as 0.54-2.49 μM compared with CS055 (2.28∼ >26 μM) and MS275 (0.47-6.74 μM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy.
|
Antiproliferative activity against human MGC803 cells at 8 uM after 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
22.4
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents.
Year : 2018
Volume : 143
First Page : 320
Last Page : 333
Authors : Xie R, Li Y, Tang P, Yuan Q.
Abstract : A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC50 values of as low as 0.54-2.49 μM compared with CS055 (2.28∼ >26 μM) and MS275 (0.47-6.74 μM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy.
|
Antiproliferative activity against human A375 cells at 2 uM after 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
13.4
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents.
Year : 2018
Volume : 143
First Page : 320
Last Page : 333
Authors : Xie R, Li Y, Tang P, Yuan Q.
Abstract : A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC50 values of as low as 0.54-2.49 μM compared with CS055 (2.28∼ >26 μM) and MS275 (0.47-6.74 μM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy.
|
Antiproliferative activity against human A375 cells at 8 uM after 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
33.5
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents.
Year : 2018
Volume : 143
First Page : 320
Last Page : 333
Authors : Xie R, Li Y, Tang P, Yuan Q.
Abstract : A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC50 values of as low as 0.54-2.49 μM compared with CS055 (2.28∼ >26 μM) and MS275 (0.47-6.74 μM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy.
|
Antiproliferative activity against human HeLa cells at 2 uM after 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
7.3
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents.
Year : 2018
Volume : 143
First Page : 320
Last Page : 333
Authors : Xie R, Li Y, Tang P, Yuan Q.
Abstract : A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC50 values of as low as 0.54-2.49 μM compared with CS055 (2.28∼ >26 μM) and MS275 (0.47-6.74 μM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy.
|
Antiproliferative activity against human HeLa cells at 8 uM after 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
24.3
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel 2-aminobenzamides containing dithiocarbamate moiety as histone deacetylase inhibitors and potent antitumor agents.
Year : 2018
Volume : 143
First Page : 320
Last Page : 333
Authors : Xie R, Li Y, Tang P, Yuan Q.
Abstract : A novel series of 2-aminobenzamides with dithiocarbamate as cap group were designed and synthesized as histone deacetylase (HDAC) inhibitors. Most newly synthesized compounds displayed potent antiproliferative activity against diverse human tumor cell lines. The most potent compounds, M101, M122 and M133 exhibited remarkably enhanced anticancer potency against 6 kinds of cancer cell lines with IC50 values of as low as 0.54-2.49 μM compared with CS055 (2.28∼ >26 μM) and MS275 (0.47-6.74 μM). HDAC isoform selectivity assay indicated that M101, M122 and M133 are HDAC1 and HDAC2 selective inhibitors. We also rationalize the high potency and selectivity of compound M122 by molecular docking. Further investigation showed that M101, M122 and M133 could inhibit colony formation of human hepatocellular carcinoma cell line SMMC7721. Furthermore, M101, M122 and M133 remarkably induced apoptosis in SMMC7721 cancer cells. M101 and M133 were found to potently induce SMMC7721 cancer cell cycle arrest at G2/M phase. This study demonstrated that introducing dithiocarbamate as the capping group of 2-aminobenzamide is effective for improving both HDAC inhibitory activity and antitumor activity. The most potent compounds, M101, M122 and M133 could be promising candidates for cancer therapy.
|
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
|
-5.26
%
|
|
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.
|
Antiproliferative activity against human A375 cells assessed as reduction in cell growth at 8 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
33.5
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human A375 cells assessed as reduction in cell growth at 2 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
13.4
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human HeLa cells assessed as reduction in cell growth at 8 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
32.4
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human HeLa cells assessed as reduction in cell growth at 2 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
13.4
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human A549 cells assessed as reduction in cell growth at 8 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
29.1
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human A549 cells assessed as reduction in cell growth at 2 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
23.5
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human HCT116 cells assessed as reduction in cell growth at 8 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
44.0
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human HCT116 cells assessed as reduction in cell growth at 2 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
13.0
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human SMMC7721 cells assessed as reduction in cell growth at 8 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
29.1
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Antiproliferative activity against human SMMC7721 cells assessed as reduction in cell growth at 2 uM incubated for 72 hrs by CCK-8 assay relative to control
|
Homo sapiens
|
23.5
%
|
|
Journal : Eur J Med Chem
Title : Design, synthesis and biological evaluation of novel thioquinazolinone-based 2-aminobenzamide derivatives as potent histone deacetylase (HDAC) inhibitors.
Year : 2019
Volume : 173
First Page : 185
Last Page : 202
Authors : Cheng C, Yun F, He J, Ullah S, Yuan Q.
Abstract : A series of novel 2-aminobenzamide derivatives decorated with thioquinazolinone were designed and synthesized as histone deacetylase (HDAC) inhibitors. These derivatives were evaluated for their antiproliferative activities against several human cancer cell lines including A375, Hela, A549, HCT116 and SMMC7721. It's significantly indicated that some inhibitors exhibited potent antiproliferative activities towards all the studied cancer cell lines. Compounds 7a, 4i, 4o, and 4p exhibited higher antiproliferative activities towards three cancer cell lines: A375, A549 and SMMC7721 compared to CS055, MS275, and CI994. Compound 4p showed more than 4000-fold the isoform selectivity for HDAC1 and more than 250-fold selectivity for HDAC2 compared with HDAC6. The molecular docking analysis reasonably explained the HDAC inhibitory activity and isoform selectivity. In addition, compounds 7a, 4i, 4o, and 4p showed potent inhibitory activities in migration assay and colony formation analysis, and also promoted cell apoptosis. Moreover, compounds 7a, 4i, and 4o inhibited the growth of SMMC7721 cells at S phase of the cell cycle. The immunofluorometric analysis indicated that compounds 7a, 4i, 4o, and 4p could increase the acetylation status of H3K9. Furthermore, in vivo anticancer efficacy of compound 4p was assessed in the A549 xenograft models, and 4p demonstrated potent antitumor activity (TGI = 62.5%). This study provided an effective strategy for further development of tumor-targeting therapy.
|
Inhibition of recombinant human full length C-terminal His/FALG-tagged HDAC1 expressed in Sf9 insect cells using FAM-labeled acetylated peptide A as substrate preincubated for 3 hrs followed by substrate addition and measured after 60 mins by fluorescence assay
|
Homo sapiens
|
41.0
nM
|
|
Journal : Eur J Med Chem
Title : Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamides.
Year : 2019
Volume : 166
First Page : 369
Last Page : 380
Authors : Amin SA, Adhikari N, Kotagiri S, Jha T, Ghosh B.
Abstract : Among numerous essential processes, memory and learning are important work of the brain. Epigenetic manipulations through histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been implicated in memory function by modulating memory storage-related gene expression. Among these HDACs, HDAC3 is found to be important in the long-term memory process. Histone deacetylase inhibitors (HDACIs) have been established to have direct involvement to enhance the memory function through upregulation of hippocampal NR2B mRNA and phosphorylation of cyclic AMP (cAMP)-response element binding (CREB) at the NR2B gene. Though HDACIs were initially implicated as potent anticancer agents, these are also found to enhance memory or ameliorate deficits in memory dysfunction. It is done through inducing a histone hyperacetylated state. HDAC3 is a negative regulator of memory and learning and thus, deletion of HDAC3 in the dorsal hippocampus may lead to an enhanced long-term memory. Therefore, identification of potential and selective HDAC3 inhibitors may be useful in ameliorating long-term memory function and learning. In this review, detail chemico-biological and structural information of HDAC3 in memory and learning functions and benzamide-based HDAC3 inhibitors has been focussed. This may help to achieve a deep insight so that potent and selective benzamide-based HDAC3 inhibitors may be designed in future to combat memory and learning-related dysfunctions.
|
Inhibition of recombinant human full length C-terminal FLAG-tagged HDAC2 expressed in Sf9 insect cells using FAM-labeled acetylated peptide A as substrate preincubated for 3 hrs followed by substrate addition and measured after 60 mins by fluorescence assay
|
Homo sapiens
|
147.0
nM
|
|
Journal : Eur J Med Chem
Title : Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamides.
Year : 2019
Volume : 166
First Page : 369
Last Page : 380
Authors : Amin SA, Adhikari N, Kotagiri S, Jha T, Ghosh B.
Abstract : Among numerous essential processes, memory and learning are important work of the brain. Epigenetic manipulations through histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been implicated in memory function by modulating memory storage-related gene expression. Among these HDACs, HDAC3 is found to be important in the long-term memory process. Histone deacetylase inhibitors (HDACIs) have been established to have direct involvement to enhance the memory function through upregulation of hippocampal NR2B mRNA and phosphorylation of cyclic AMP (cAMP)-response element binding (CREB) at the NR2B gene. Though HDACIs were initially implicated as potent anticancer agents, these are also found to enhance memory or ameliorate deficits in memory dysfunction. It is done through inducing a histone hyperacetylated state. HDAC3 is a negative regulator of memory and learning and thus, deletion of HDAC3 in the dorsal hippocampus may lead to an enhanced long-term memory. Therefore, identification of potential and selective HDAC3 inhibitors may be useful in ameliorating long-term memory function and learning. In this review, detail chemico-biological and structural information of HDAC3 in memory and learning functions and benzamide-based HDAC3 inhibitors has been focussed. This may help to achieve a deep insight so that potent and selective benzamide-based HDAC3 inhibitors may be designed in future to combat memory and learning-related dysfunctions.
|
Inhibition of recombinant human full length HDAC3 using FAM-labeled acetylated peptide A as substrate preincubated for 3 hrs followed by substrate addition and measured after 60 mins by fluorescence assay
|
Homo sapiens
|
46.0
nM
|
|
Journal : Eur J Med Chem
Title : Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamides.
Year : 2019
Volume : 166
First Page : 369
Last Page : 380
Authors : Amin SA, Adhikari N, Kotagiri S, Jha T, Ghosh B.
Abstract : Among numerous essential processes, memory and learning are important work of the brain. Epigenetic manipulations through histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been implicated in memory function by modulating memory storage-related gene expression. Among these HDACs, HDAC3 is found to be important in the long-term memory process. Histone deacetylase inhibitors (HDACIs) have been established to have direct involvement to enhance the memory function through upregulation of hippocampal NR2B mRNA and phosphorylation of cyclic AMP (cAMP)-response element binding (CREB) at the NR2B gene. Though HDACIs were initially implicated as potent anticancer agents, these are also found to enhance memory or ameliorate deficits in memory dysfunction. It is done through inducing a histone hyperacetylated state. HDAC3 is a negative regulator of memory and learning and thus, deletion of HDAC3 in the dorsal hippocampus may lead to an enhanced long-term memory. Therefore, identification of potential and selective HDAC3 inhibitors may be useful in ameliorating long-term memory function and learning. In this review, detail chemico-biological and structural information of HDAC3 in memory and learning functions and benzamide-based HDAC3 inhibitors has been focussed. This may help to achieve a deep insight so that potent and selective benzamide-based HDAC3 inhibitors may be designed in future to combat memory and learning-related dysfunctions.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-12.87
%
|
|
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.
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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
|
1.92
%
|
|
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
|
1.92
%
|
|
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.
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Inhibition of recombinant human C-terminal His/FLAG-tagged HDAC1 (1 to 482 residues) expressed in Sf9 insect cells using Boc-Lys(epsilon-Ac)-AMC as substrate measured after 90 mins by fluorescence assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Eur J Med Chem
Title : Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC).
Year : 2020
Volume : 208
First Page : 112800
Last Page : 112800
Authors : Cao F,de Weerd S,Chen D,Zwinderman MRH,van der Wouden PE,Dekker FJ
Abstract : Histone deacetylases (HDACs) play important roles in inflammatory diseases like asthma and chronic obstructive pulmonary disease (COPD). Unravelling of and interfering with the functions of specific isoenzymes contributing to inflammation provides opportunities for drug development. Here we synthesize proteolysis targeting chimeras (PROTACs) for degradation of class I HDACs in which o-aminoanilide-based class I HDAC inhibitors are tethered to the cereblon ligand pomalidomide. One of these PROTACs, denoted HD-TAC7, showed promising degradation effects for HDAC3 with a DC value of 0.32 μM. In contrast to biochemical evidence using siRNA, HD-TAC7 showed a minimal effect on gene expression in LPS/IFNγ-stimulated RAW 264.7 macrophages. The lack of effect can be attributed to downregulation of the NF-κB subunit p65, which is a known side effect of pomalidomide treatment. Altogether, we describe a novel PROTAC that enables selective downregulation of HDAC3 levels, however we note that concomitant downregulation of the NF-κB subunit p65 can confound the biological outcome.
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Inhibition of recombinant human full-length C-terminal FLAG-tagged HDAC2 expressed in baculovirus infected Sf9 insect cells using Boc-Lys(epsilon-Ac)-AMC as substrate measured after 90 mins by fluorescence assay
|
Homo sapiens
|
830.0
nM
|
|
Journal : Eur J Med Chem
Title : Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC).
Year : 2020
Volume : 208
First Page : 112800
Last Page : 112800
Authors : Cao F,de Weerd S,Chen D,Zwinderman MRH,van der Wouden PE,Dekker FJ
Abstract : Histone deacetylases (HDACs) play important roles in inflammatory diseases like asthma and chronic obstructive pulmonary disease (COPD). Unravelling of and interfering with the functions of specific isoenzymes contributing to inflammation provides opportunities for drug development. Here we synthesize proteolysis targeting chimeras (PROTACs) for degradation of class I HDACs in which o-aminoanilide-based class I HDAC inhibitors are tethered to the cereblon ligand pomalidomide. One of these PROTACs, denoted HD-TAC7, showed promising degradation effects for HDAC3 with a DC value of 0.32 μM. In contrast to biochemical evidence using siRNA, HD-TAC7 showed a minimal effect on gene expression in LPS/IFNγ-stimulated RAW 264.7 macrophages. The lack of effect can be attributed to downregulation of the NF-κB subunit p65, which is a known side effect of pomalidomide treatment. Altogether, we describe a novel PROTAC that enables selective downregulation of HDAC3 levels, however we note that concomitant downregulation of the NF-κB subunit p65 can confound the biological outcome.
|
Inhibition of human recombinant C-terminal His-tagged HDAC3 (1 to 428 residues)/N-terminal GST-tagged NCOR2 (395 to 489 residues) expressed in baculovirus infected Sf9 insect cells using Boc-Lys(epsilon-Ac)-AMC as substrate measured after 90 mins by fluorescence assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : Eur J Med Chem
Title : Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC).
Year : 2020
Volume : 208
First Page : 112800
Last Page : 112800
Authors : Cao F,de Weerd S,Chen D,Zwinderman MRH,van der Wouden PE,Dekker FJ
Abstract : Histone deacetylases (HDACs) play important roles in inflammatory diseases like asthma and chronic obstructive pulmonary disease (COPD). Unravelling of and interfering with the functions of specific isoenzymes contributing to inflammation provides opportunities for drug development. Here we synthesize proteolysis targeting chimeras (PROTACs) for degradation of class I HDACs in which o-aminoanilide-based class I HDAC inhibitors are tethered to the cereblon ligand pomalidomide. One of these PROTACs, denoted HD-TAC7, showed promising degradation effects for HDAC3 with a DC value of 0.32 μM. In contrast to biochemical evidence using siRNA, HD-TAC7 showed a minimal effect on gene expression in LPS/IFNγ-stimulated RAW 264.7 macrophages. The lack of effect can be attributed to downregulation of the NF-κB subunit p65, which is a known side effect of pomalidomide treatment. Altogether, we describe a novel PROTAC that enables selective downregulation of HDAC3 levels, however we note that concomitant downregulation of the NF-κB subunit p65 can confound the biological outcome.
|
Inhibition of HDAC2-CoREST-LSD1 (unknown origin) using Boc- (Ac)Lys-AMC as substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by fluorescent assay
|
Homo sapiens
|
620.0
nM
|
|
|
Inhibition of HDAC1-CoREST-LSD1 (unknown origin) using Boc- (Ac)Lys-AMC as substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by fluorescent assay
|
Homo sapiens
|
530.0
nM
|
|
|
Inhibition of HDAC3-SMRT (unknown origin) using Boc- (Ac)Lys-AMC as substrate preincubated for 1 hr followed by substrate addition and measured after 1 hr by fluorescent assay
|
Homo sapiens
|
130.0
nM
|
|
