|
Inhibition of HDAC8 (unknown origin) using tripeptide MAZ-1675 as substrate after 30 mins
|
Homo sapiens
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Development and therapeutic implications of selective histone deacetylase 6 inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6297
Last Page : 6313
Authors : Kalin JH, Bergman JA.
Abstract : This Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions, and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency, and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented.
|
Inhibition of HDAC6 (unknown origin) using fluorophore tripeptide as substrate after 30 mins
|
Homo sapiens
|
4.7
nM
|
|
Journal : J. Med. Chem.
Title : Development and therapeutic implications of selective histone deacetylase 6 inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6297
Last Page : 6313
Authors : Kalin JH, Bergman JA.
Abstract : This Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions, and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency, and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented.
|
Inhibition of HDAC3 (unknown origin) using fluorophore tripeptide as substrate after 30 mins
|
Homo sapiens
|
51.0
nM
|
|
Journal : J. Med. Chem.
Title : Development and therapeutic implications of selective histone deacetylase 6 inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6297
Last Page : 6313
Authors : Kalin JH, Bergman JA.
Abstract : This Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions, and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency, and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented.
|
Inhibition of HDAC2 (unknown origin) using fluorophore tripeptide as substrate after 30 mins
|
Homo sapiens
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : Development and therapeutic implications of selective histone deacetylase 6 inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6297
Last Page : 6313
Authors : Kalin JH, Bergman JA.
Abstract : This Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions, and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency, and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented.
|
Inhibition of HDAC1 (unknown origin) using fluorophore tripeptide as substrate after 30 mins
|
Homo sapiens
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Development and therapeutic implications of selective histone deacetylase 6 inhibitors.
Year : 2013
Volume : 56
Issue : 16
First Page : 6297
Last Page : 6313
Authors : Kalin JH, Bergman JA.
Abstract : This Perspective provides an in depth look at the numerous disease states in which histone deacetylase 6 (HDAC6) has been implicated. The physiological pathways, protein-protein interactions, and non-histone substrates relating to different pathological conditions are discussed with regard to HDAC6. Furthermore, the compounds and methods used to modulate HDAC6 activity are profiled. The latter half of this Perspective analyzes reported HDAC6 selective inhibitors in terms of structure, potency, and selectivity over the other HDAC isoforms with the intent of providing a comprehensive overview of the molecular tools available. Potential obstacles and future directions of HDAC6 research are also presented.
|
Inhibition of HDAC1 (unknown origin) using RHKK(Ac) (379 to 382) p53 peptide as substrate by fluorescence assay
|
Homo sapiens
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells.
Year : 2014
Volume : 57
Issue : 10
First Page : 4009
Last Page : 4022
Authors : Lee HY, Tsai AC, Chen MC, Shen PJ, Cheng YC, Kuo CC, Pan SL, Liu YM, Liu JF, Yeh TK, Wang JC, Chang CY, Chang JY, Liou JP.
Abstract : A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 μM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N'-phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.
|
Inhibition of HDAC2 (unknown origin) using RHKK(Ac) (379 to 382) p53 peptide as substrate by fluorescence assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : J. Med. Chem.
Title : Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells.
Year : 2014
Volume : 57
Issue : 10
First Page : 4009
Last Page : 4022
Authors : Lee HY, Tsai AC, Chen MC, Shen PJ, Cheng YC, Kuo CC, Pan SL, Liu YM, Liu JF, Yeh TK, Wang JC, Chang CY, Chang JY, Liou JP.
Abstract : A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 μM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N'-phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.
|
Inhibition of HDAC6 (unknown origin) using RHKK(Ac) (379 to 382) p53 peptide as substrate by fluorescence assay
|
Homo sapiens
|
4.7
nM
|
|
Journal : J. Med. Chem.
Title : Azaindolylsulfonamides, with a more selective inhibitory effect on histone deacetylase 6 activity, exhibit antitumor activity in colorectal cancer HCT116 cells.
Year : 2014
Volume : 57
Issue : 10
First Page : 4009
Last Page : 4022
Authors : Lee HY, Tsai AC, Chen MC, Shen PJ, Cheng YC, Kuo CC, Pan SL, Liu YM, Liu JF, Yeh TK, Wang JC, Chang CY, Chang JY, Liou JP.
Abstract : A series of indolylsulfonylcinnamic hydroxamates has been synthesized. Compound 12, (E)-3-(3-((1H-pyrrolo[2,3-b]pyridin-1-yl)sulfonyl)phenyl)-N-hydroxyacrylamide, which has a 7-azaindole core cap, was shown to have antiproliferative activity against KB, H460, PC3, HSC-3, HONE-1, A549, MCF-7, TSGH, MKN45, HT29, and HCT116 human cancer cell lines. Pharmacological studies indicated that 12 functions as a potent HDAC inhibitor with an IC50 value of 0.1 μM. It is highly selective for histone deacetylase 6 (HDAC6) and is 60-fold more active than against HDAC1 and 223-fold more active than against HDAC2. It has a good pharmacokinetic profile with oral bioavailability of 33%. In in vivo efficacy evaluations in colorectal HCT116 xenografts, compound 12 suppresses tumor growth more effectively than SAHA (1, N-hydroxy-N'-phenyloctanediamide) and is therefore seen as a suitable candidate for further investigation.
|
Enzyme Assays: Compounds for testing were diluted in DMSO to 50 fold the final concentration and a ten point three fold dilution series was made. The compounds were diluted in assay buffer (50 mM HEPES, pH 7.4, 100 mM KCl, 0.001% Tween-20, 0.05% BSA, 20 uM TCEP) to 6 fold their final concentration. The HDAC enzymes (purchased from BPS Biosciences) were diluted to 1.5 fold their final concentration in assay buffer. The tripeptide substrate and trypsin at 0.05 uM final concentration were diluted in assay buffer at 6 fold their final concentration. The final enzyme concentrations used in these assays were 3.3 ng/ml (HDAC1), 0.2 ng/ml (HDAC2), 0.08 ng/ml (HDAC3) and 2 ng/ml (HDAC6). The final substrate concentrations used were 16 uM (HDAC1), 10 uM (HDAC2), 17 uM (HDAC3) and 14 uM (HDAC6).
|
Homo sapiens
|
10.0
nM
|
|
Enzyme Assays: Compounds for testing were diluted in DMSO to 50 fold the final concentration and a ten point three fold dilution series was made. The compounds were diluted in assay buffer (50 mM HEPES, pH 7.4, 100 mM KCl, 0.001% Tween-20, 0.05% BSA, 20 uM TCEP) to 6 fold their final concentration. The HDAC enzymes (purchased from BPS Biosciences) were diluted to 1.5 fold their final concentration in assay buffer. The tripeptide substrate and trypsin at 0.05 uM final concentration were diluted in assay buffer at 6 fold their final concentration. The final enzyme concentrations used in these assays were 3.3 ng/ml (HDAC1), 0.2 ng/ml (HDAC2), 0.08 ng/ml (HDAC3) and 2 ng/ml (HDAC6). The final substrate concentrations used were 16 uM (HDAC1), 10 uM (HDAC2), 17 uM (HDAC3) and 14 uM (HDAC6).
|
Homo sapiens
|
84.0
nM
|
|
Title : Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof
Year : 2013
|
Inhibition of human recombinant HDAC1 using AMC labeled AC-peptide as substrate incubated for 1 hr by fluorescence analysis
|
Homo sapiens
|
38.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer.
Year : 2016
Volume : 59
Issue : 4
First Page : 1455
Last Page : 1470
Authors : Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, Long C, Tang M, Cao D, Wang X, Xiang W, Yi Y, Ma L, You J, Chen L.
Abstract : Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.
|
Inhibition of human recombinant HDAC6 using AMC labeled AC-peptide as substrate incubated for 1 hr by fluorescence analysis
|
Homo sapiens
|
9.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer.
Year : 2016
Volume : 59
Issue : 4
First Page : 1455
Last Page : 1470
Authors : Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, Long C, Tang M, Cao D, Wang X, Xiang W, Yi Y, Ma L, You J, Chen L.
Abstract : Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.
|
Inhibition of human recombinant HDAC8 using AMC labeled AC-peptide as substrate incubated for 1 hr by fluorescence analysis
|
Homo sapiens
|
254.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer.
Year : 2016
Volume : 59
Issue : 4
First Page : 1455
Last Page : 1470
Authors : Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, Long C, Tang M, Cao D, Wang X, Xiang W, Yi Y, Ma L, You J, Chen L.
Abstract : Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.
|
Inhibition of recombinant HDAC2 (unknown origin) using AMC labeled AC-peptide as substrate incubated for 1 hr by fluorescence analysis
|
Homo sapiens
|
95.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer.
Year : 2016
Volume : 59
Issue : 4
First Page : 1455
Last Page : 1470
Authors : Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, Long C, Tang M, Cao D, Wang X, Xiang W, Yi Y, Ma L, You J, Chen L.
Abstract : Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.
|
Inhibition of recombinant HDAC3 (unknown origin) using AMC labeled AC-peptide as substrate incubated for 1 hr by fluorescence analysis
|
Homo sapiens
|
135.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer.
Year : 2016
Volume : 59
Issue : 4
First Page : 1455
Last Page : 1470
Authors : Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, Long C, Tang M, Cao D, Wang X, Xiang W, Yi Y, Ma L, You J, Chen L.
Abstract : Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.
|
Inhibition of recombinant HDAC10 (unknown origin) using AMC labeled AC-peptide as substrate incubated for 1 hr by fluorescence analysis
|
Homo sapiens
|
194.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Selective Histone Deacetylase 6 Inhibitors Using the Quinazoline as the Cap for the Treatment of Cancer.
Year : 2016
Volume : 59
Issue : 4
First Page : 1455
Last Page : 1470
Authors : Yang Z, Wang T, Wang F, Niu T, Liu Z, Chen X, Long C, Tang M, Cao D, Wang X, Xiang W, Yi Y, Ma L, You J, Chen L.
Abstract : Novel selective histone deacetylase 6 (HDAC6) inhibitors using the quinazoline as the cap were designed, synthesized, and evaluated for HDAC enzymatic assays. N-Hydroxy-4-(2-methoxy-5-(methyl(2-methylquinazolin-4-yl)amino)phenoxy)butanamide, 23bb, was the most potent selective inhibitor for HDAC6 with an IC50 of 17 nM and showed 25-fold and 200-fold selectivity relative to HDAC1 and HDAC8, respectively. In vitro, 23bb presented low nanomolar antiproliferative effects against panel of cancer cell lines. Western blot analysis further confirmed that 23bb increased acetylation level of α-tubulin in vitro. 23bb has a good pharmacokinetic profile with oral bioavailability of 47.0% in rats. In in vivo efficacy evaluations of colorectal HCT116, acute myelocytic leukemia MV4-11, and B cell lymphoma Romas xenografts, 23bb more effectively inhibited the tumor growth than SAHA even at a 4-fold reduced dose or ACY-1215 at the same dose. Our results indicated that 23bb is a potent oral anticancer candidate for selective HDAC6 inhibitor and deserves further investigation.
|
Inhibition of full length human recombinant C-terminal FLAG-His-tagged HDAC1 expressed in Sf9 cells using FTS as substrate preincubated for 10 mins followed by substrate addition measured over 30 mins
|
Homo sapiens
|
58.0
nM
|
|
Journal : Eur J Med Chem
Title : Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms.
Year : 2017
Volume : 127
First Page : 115
Last Page : 127
Authors : Nepali K, Lee HY, Lai MJ, Ojha R, Wu TY, Wu GX, Chen MC, Liou JP.
Abstract : This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5-18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs.
|
Inhibition of full length human recombinant C-terminal FLAG-tagged HDAC2 expressed in Sf9 cells using FTS as substrate preincubated for 10 mins followed by substrate addition measured over 30 mins
|
Homo sapiens
|
48.0
nM
|
|
Journal : Eur J Med Chem
Title : Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms.
Year : 2017
Volume : 127
First Page : 115
Last Page : 127
Authors : Nepali K, Lee HY, Lai MJ, Ojha R, Wu TY, Wu GX, Chen MC, Liou JP.
Abstract : This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5-18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs.
|
Inhibition of full length human recombinant N-terminal GST-tagged HDAC6 expressed in Sf9 cells using FTS as substrate preincubated for 10 mins followed by substrate addition measured over 30 mins
|
Homo sapiens
|
4.7
nM
|
|
Journal : Eur J Med Chem
Title : Ring-opened tetrahydro-γ-carbolines display cytotoxicity and selectivity with histone deacetylase isoforms.
Year : 2017
Volume : 127
First Page : 115
Last Page : 127
Authors : Nepali K, Lee HY, Lai MJ, Ojha R, Wu TY, Wu GX, Chen MC, Liou JP.
Abstract : This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5-18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substituted indoles (compounds 7, 11, and 15) which showed significant improvements of selective inhibition for HDAC6 over HDAC1 and HDAC2 in comparison to ACY1215, a compound undergoing clinical trials. In addition, attachment of different hydroxamic acid groups, the zinc binding motif at the N1 position, contributes to the antiproliferative activity in cancer cells. Several synthetic compounds exhibited potent growth inhibition in a broad spectrum of tumor cell lines, induced irreversible growth arrest capacities by suppressing colony formation ability and activated the apoptosis pathway. The data provide compelling evidence that our newly synthesized compounds with type B to D hydroxamic acid groups as the zinc binding motif at the N1 position are potent selective inhibitors of HDAC6 and could be investigated preclinically as potential anticancer drugs.
|
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 full length recombinant human N-terminal GST-tagged HDAC6 expressed in baculovirus infected insect cells using RHK-K(Ac)-AMC as substrate after 90 mins by fluorescence assay
|
Homo sapiens
|
4.7
nM
|
|
Journal : J Med Chem
Title : (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo.
Year : 2018
Volume : 61
Issue : 3
First Page : 905
Last Page : 917
Authors : Lee HY, Nepali K, Huang FI, Chang CY, Lai MJ, Li YH, Huang HL, Yang CR, Liou JP.
Abstract : A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4,000-43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.
|
Inhibition of full length recombinant human C-terminal FLAG/His-tagged HDAC1 expressed in baculovirus infected sf21 cells using RHK-K(Ac)-AMC as substrate after 60 mins by fluorescence assay
|
Homo sapiens
|
58.0
nM
|
|
Journal : J Med Chem
Title : (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo.
Year : 2018
Volume : 61
Issue : 3
First Page : 905
Last Page : 917
Authors : Lee HY, Nepali K, Huang FI, Chang CY, Lai MJ, Li YH, Huang HL, Yang CR, Liou JP.
Abstract : A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4,000-43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.
|
Inhibition of full length recombinant human C-terminal GST-tagged HDAC2 expressed in baculovirus infected insect cells using RHK-K(Ac)-AMC as substrate after 60 mins by fluorescence assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : J Med Chem
Title : (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo.
Year : 2018
Volume : 61
Issue : 3
First Page : 905
Last Page : 917
Authors : Lee HY, Nepali K, Huang FI, Chang CY, Lai MJ, Li YH, Huang HL, Yang CR, Liou JP.
Abstract : A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4,000-43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.
|
Inhibition of full length recombinant human C-terminal His-tagged HDAC3/N-terminal GST-tagged NCOR2 (395 to 489 residues) expressed in insect cells using RHK-K(Ac)-AMC as substrate after 60 mins by fluorescence assay
|
Homo sapiens
|
51.0
nM
|
|
Journal : J Med Chem
Title : (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo.
Year : 2018
Volume : 61
Issue : 3
First Page : 905
Last Page : 917
Authors : Lee HY, Nepali K, Huang FI, Chang CY, Lai MJ, Li YH, Huang HL, Yang CR, Liou JP.
Abstract : A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4,000-43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.
|
Inhibition of recombinant human C-terminal His-tagged/N-terminal Strep2-tagged HDAC8 (1 to 377 residues) expressed in insect cells using RHK-K(Ac)-AMC as substrate after 60 mins by fluorescence assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : (N-Hydroxycarbonylbenylamino)quinolines as Selective Histone Deacetylase 6 Inhibitors Suppress Growth of Multiple Myeloma in Vitro and in Vivo.
Year : 2018
Volume : 61
Issue : 3
First Page : 905
Last Page : 917
Authors : Lee HY, Nepali K, Huang FI, Chang CY, Lai MJ, Li YH, Huang HL, Yang CR, Liou JP.
Abstract : A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4,000-43,000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferative activity against human multiple myeloma RPMI 8226, U266, and NCI-H929 cells with no effect on normal bone marrow cells. Compound 13, as a single drug, suppresses the growth of tumors by a %TGI factor of 60.4% in human multiple myeloma RPMI 8226 xenograft models and, in combination with bortezomib, shows significant in vivo antitumor activity (%TGI = 86.2%). Compound 13 also demonstrates good human hepatocytic stability and high permeability, without any effect on mutagenicity and cytotoxicity. Thus, compound 13 is a potent HDAC6 inhibitor that could be developed for the treatment of multiple myeloma in the future.
|
Cytotoxicity against human BCP-ALL cells derived from patient 1 after 72 hrs by CellTiter-Glo luminescent cell viability assay
|
Homo sapiens
|
290.0
nM
|
|
Journal : J Med Chem
Title : Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor.
Year : 2018
Volume : 61
Issue : 22
First Page : 10299
Last Page : 10309
Authors : Bhatia S, Krieger V, Groll M, Osko JD, Reßing N, Ahlert H, Borkhardt A, Kurz T, Christianson DW, Hauer J, Hansen FK.
Abstract : Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies.
|
Cytotoxicity against human BCP-ALL cells derived from patient 2 after 72 hrs by CellTiter-Glo luminescent cell viability assay
|
Homo sapiens
|
580.0
nM
|
|
Journal : J Med Chem
Title : Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor.
Year : 2018
Volume : 61
Issue : 22
First Page : 10299
Last Page : 10309
Authors : Bhatia S, Krieger V, Groll M, Osko JD, Reßing N, Ahlert H, Borkhardt A, Kurz T, Christianson DW, Hauer J, Hansen FK.
Abstract : Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies.
|
Cytotoxicity against human BCP-ALL cells derived from patient 4 after 72 hrs by CellTiter-Glo luminescent cell viability assay
|
Homo sapiens
|
540.0
nM
|
|
Journal : J Med Chem
Title : Discovery of the First-in-Class Dual Histone Deacetylase-Proteasome Inhibitor.
Year : 2018
Volume : 61
Issue : 22
First Page : 10299
Last Page : 10309
Authors : Bhatia S, Krieger V, Groll M, Osko JD, Reßing N, Ahlert H, Borkhardt A, Kurz T, Christianson DW, Hauer J, Hansen FK.
Abstract : Dual- or multitarget drugs have emerged as a promising alternative to combination therapies. Proteasome inhibitors (PIs) possess synergistic activity with histone deacetylase (HDAC) inhibitors due to the simultaneous blockage of the ubiquitin degradation and aggresome pathways. Here, we present the design, synthesis, binding modes, and anticancer properties of RTS-V5 as the first-in-class dual HDAC-proteasome ligand. The inhibition of both targets was confirmed by biochemical and cellular assays as well as X-ray crystal structures of the 20S proteasome and HDAC6 complexed with RTS-V5. Cytotoxicity assays with leukemia and multiple myeloma cell lines as well as therapy refractory primary patient-derived leukemia cells demonstrated that RTS-V5 possesses potent and selective anticancer activity. Our results will thus guide the structure-based optimization of dual HDAC-proteasome inhibitors for the treatment of hematological malignancies.
|
Inhibition of HDAC1 (unknown origin)
|
Homo sapiens
|
58.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease.
Year : 2018
Volume : 150
First Page : 506
Last Page : 524
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.
|
Inhibition of HDAC2 (unknown origin)
|
Homo sapiens
|
48.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease.
Year : 2018
Volume : 150
First Page : 506
Last Page : 524
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.
|
Inhibition of HDAC3 (unknown origin)
|
Homo sapiens
|
51.0
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease.
Year : 2018
Volume : 150
First Page : 506
Last Page : 524
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.
|
Inhibition of HDAC6 (unknown origin)
|
Homo sapiens
|
4.7
nM
|
|
Journal : Eur J Med Chem
Title : Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of Alzheimer's disease.
Year : 2018
Volume : 150
First Page : 506
Last Page : 524
Authors : Rabal O, Sánchez-Arias JA, Cuadrado-Tejedor M, de Miguel I, Pérez-González M, García-Barroso C, Ugarte A, Estella-Hermoso de Mendoza A, Sáez E, Espelosin M, Ursua S, Haizhong T, Wei W, Musheng X, Garcia-Osta A, Oyarzabal J.
Abstract : We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.
|
Inhibition of full length recombinant human C-terminal FLAG/His-tagged HDAC1 expressed in baculovirus infected sf9 cells using Boc-Lys-(Ac)-AMC as substrate preincubated for 15 mins followed by substrate addition measured after 60 mins by fluorescence assay
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif.
Year : 2018
Volume : 26
Issue : 8
First Page : 1418
Last Page : 1425
Authors : Yang J, Cheng G, Xu Q, Luan S, Wang S, Liu D, Zhao L.
Abstract : In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020µM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1' of pyrazol gave the most selectivity. The most compounds 11i (GI50=3.63μM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.
|
Inhibition of full length recombinant human C-terminal His-tagged HDAC2 expressed in baculovirus infected sf9 cells using Boc-Lys-(Ac)-AMC as substrate preincubated for 15 mins followed by substrate addition measured after 60 mins by fluorescence assay
|
Homo sapiens
|
66.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif.
Year : 2018
Volume : 26
Issue : 8
First Page : 1418
Last Page : 1425
Authors : Yang J, Cheng G, Xu Q, Luan S, Wang S, Liu D, Zhao L.
Abstract : In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020µM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1' of pyrazol gave the most selectivity. The most compounds 11i (GI50=3.63μM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.
|
Inhibition of full length recombinant human C-terminal His-tagged HDAC3/N-terminal GST-tagged NCOR2 (395 to 489 residues) expressed in baculovirus infected sf9 cells using Boc-Lys-(Ac)-AMC as substrate preincubated for 15 mins followed by substrate addition measured after 60 mins by fluorescence assay
|
Homo sapiens
|
37.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif.
Year : 2018
Volume : 26
Issue : 8
First Page : 1418
Last Page : 1425
Authors : Yang J, Cheng G, Xu Q, Luan S, Wang S, Liu D, Zhao L.
Abstract : In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020µM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1' of pyrazol gave the most selectivity. The most compounds 11i (GI50=3.63μM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.
|
Inhibition of full length recombinant human N-terminal GST-tagged HDAC6 expressed in baculovirus infected sf9 cells using Boc-Lys-(Ac)-AMC as substrate preincubated for 15 mins followed by substrate addition measured after 60 mins by fluorescence assay
|
Homo sapiens
|
9.0
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif.
Year : 2018
Volume : 26
Issue : 8
First Page : 1418
Last Page : 1425
Authors : Yang J, Cheng G, Xu Q, Luan S, Wang S, Liu D, Zhao L.
Abstract : In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020µM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1' of pyrazol gave the most selectivity. The most compounds 11i (GI50=3.63μM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.
|
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
|
2.27
%
|
|
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.
|
Inhibition of HADC6 (unknown origin)
|
Homo sapiens
|
4.7
nM
|
|
Journal : J Med Chem
Title : Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases.
Year : 2020
Volume : 63
Issue : 1
First Page : 23
Last Page : 39
Authors : Brindisi M, Saraswati AP, Brogi S, Gemma S, Butini S, Campiani G.
Abstract : Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond their well-characterized role as histone modifiers, HDACs also interact with several nonhistone substrates and their increased expression has been highlighted in specific diseases. The HDAC6 isoform, due to its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, and peroxiredoxins. HDAC6 also exerts noncatalytic activities through its interaction with ubiquitin. Both catalytic and noncatalytic functions of HDACs are being actively studied in the field of specific rare disorders beyond the well-established role in carcinogenesis. This Perspective outlines the application of HDAC(6) inhibitors in rare diseases, such as Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, and Charcot-Marie-Tooth disease, highlighting their therapeutic potential as innovative and targeted disease-modifying agents.
|
Inhibition of HADC1 (unknown origin)
|
Homo sapiens
|
58.0
nM
|
|
Journal : J Med Chem
Title : Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases.
Year : 2020
Volume : 63
Issue : 1
First Page : 23
Last Page : 39
Authors : Brindisi M, Saraswati AP, Brogi S, Gemma S, Butini S, Campiani G.
Abstract : Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond their well-characterized role as histone modifiers, HDACs also interact with several nonhistone substrates and their increased expression has been highlighted in specific diseases. The HDAC6 isoform, due to its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, and peroxiredoxins. HDAC6 also exerts noncatalytic activities through its interaction with ubiquitin. Both catalytic and noncatalytic functions of HDACs are being actively studied in the field of specific rare disorders beyond the well-established role in carcinogenesis. This Perspective outlines the application of HDAC(6) inhibitors in rare diseases, such as Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, and Charcot-Marie-Tooth disease, highlighting their therapeutic potential as innovative and targeted disease-modifying agents.
|
Inhibition of HADC2 (unknown origin)
|
Homo sapiens
|
48.0
nM
|
|
Journal : J Med Chem
Title : Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases.
Year : 2020
Volume : 63
Issue : 1
First Page : 23
Last Page : 39
Authors : Brindisi M, Saraswati AP, Brogi S, Gemma S, Butini S, Campiani G.
Abstract : Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond their well-characterized role as histone modifiers, HDACs also interact with several nonhistone substrates and their increased expression has been highlighted in specific diseases. The HDAC6 isoform, due to its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, and peroxiredoxins. HDAC6 also exerts noncatalytic activities through its interaction with ubiquitin. Both catalytic and noncatalytic functions of HDACs are being actively studied in the field of specific rare disorders beyond the well-established role in carcinogenesis. This Perspective outlines the application of HDAC(6) inhibitors in rare diseases, such as Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, and Charcot-Marie-Tooth disease, highlighting their therapeutic potential as innovative and targeted disease-modifying agents.
|
Inhibition of HADC3 (unknown origin)
|
Homo sapiens
|
51.0
nM
|
|
Journal : J Med Chem
Title : Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases.
Year : 2020
Volume : 63
Issue : 1
First Page : 23
Last Page : 39
Authors : Brindisi M, Saraswati AP, Brogi S, Gemma S, Butini S, Campiani G.
Abstract : Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond their well-characterized role as histone modifiers, HDACs also interact with several nonhistone substrates and their increased expression has been highlighted in specific diseases. The HDAC6 isoform, due to its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, and peroxiredoxins. HDAC6 also exerts noncatalytic activities through its interaction with ubiquitin. Both catalytic and noncatalytic functions of HDACs are being actively studied in the field of specific rare disorders beyond the well-established role in carcinogenesis. This Perspective outlines the application of HDAC(6) inhibitors in rare diseases, such as Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, and Charcot-Marie-Tooth disease, highlighting their therapeutic potential as innovative and targeted disease-modifying agents.
|
Inhibition of HADC8 (unknown origin)
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases.
Year : 2020
Volume : 63
Issue : 1
First Page : 23
Last Page : 39
Authors : Brindisi M, Saraswati AP, Brogi S, Gemma S, Butini S, Campiani G.
Abstract : Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond their well-characterized role as histone modifiers, HDACs also interact with several nonhistone substrates and their increased expression has been highlighted in specific diseases. The HDAC6 isoform, due to its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, and peroxiredoxins. HDAC6 also exerts noncatalytic activities through its interaction with ubiquitin. Both catalytic and noncatalytic functions of HDACs are being actively studied in the field of specific rare disorders beyond the well-established role in carcinogenesis. This Perspective outlines the application of HDAC(6) inhibitors in rare diseases, such as Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, and Charcot-Marie-Tooth disease, highlighting their therapeutic potential as innovative and targeted disease-modifying agents.
|
Inhibition of human HDAC6 using (Z-(Ac)Lys-AMC) as substrate after 90 mins by fluorescence analysis
|
Homo sapiens
|
4.7
nM
|
|
Journal : Eur J Med Chem
Title : Highly fluorescent and HDAC6 selective scriptaid analogues.
Year : 2019
Volume : 162
First Page : 321
Last Page : 333
Authors : Fleming CL, Natoli A, Schreuders J, Devlin M, Yoganantharajah P, Gibert Y, Leslie KG, New EJ, Ashton TD, Pfeffer FM.
Abstract : Fluorescent scriptaid analogues with excellent HDAC6 selectivity (HDAC1/6 > 500) and potency (HDAC6 IC<sub>50</sub> < 5 nM) have been synthesised and evaluated. The highly fluorescent nature of the compounds (up to Φ<sub>F</sub> = 0.83 in DMSO and 0.38 in aqueous buffer) makes them ideally suited for cellular imaging and visualisation of their cytoplasmic localisation was readily accomplished. Whole organism imaging in zebrafish confirmed both the vascular localisation of the new inhibitors and the impact of HDAC6 inhibition on in vivo development.
|
Inhibition of full length recombinant human C-terminal FLAG-tagged HDAC1 expressed in sf9 cells preincubated for 5 mins followed by biotinylated H3K9-Ac substrate addition and measured after 60 mins by HTRF assay
|
Homo sapiens
|
74.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma.
Year : 2019
Volume : 29
Issue : 3
First Page : 349
Last Page : 352
Authors : Zhou R, Fang S, Zhang M, Zhang Q, Hu J, Wang M, Wang C, Zhu J, Shen A, Chen X, Zheng C.
Abstract : Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e-7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.
|
Inhibition of full length recombinant human N-terminal GST-tagged HDAC6 expressed in baculovirus infected sf9 cells preincubated for 5 mins followed by biotinylated H3K9-Ac substrate addition and measured after 60 mins by HTRF assay
|
Homo sapiens
|
5.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis, and bioactivity evaluation of novel Bcl-2/HDAC dual-target inhibitors for the treatment of multiple myeloma.
Year : 2019
Volume : 29
Issue : 3
First Page : 349
Last Page : 352
Authors : Zhou R, Fang S, Zhang M, Zhang Q, Hu J, Wang M, Wang C, Zhu J, Shen A, Chen X, Zheng C.
Abstract : Multiple myeloma (MM) is the second most common haematological malignancy. Almost all patients with MM eventually relapse, and most recommended treatment protocols for the patients with relapsed refractory MM comprise a combination of drugs with different mechanisms of action. Therefore novel drugs are in urgent need in clinic. Bcl-2 inhibitors and HDAC inhibitors were proved their anti-MM effect in clinic or under clinical trials, and they were further discovered to have synergistic interactions. In this study, a series of Bcl-2/HDAC dual-target inhibitors were designed and synthesized. Among them, compounds 7e-7g showed good inhibitory activities against HDAC6 and high binding affinities to Bcl-2 protein simultaneously. They also displayed good growth inhibitory activities against human MM cell line RPMI-8226, which proved their potential value for the treatment of multiple myeloma.
|
Inhibition of HDAC1 (unknown origin)
|
Homo sapiens
|
187.9
nM
|
|
Journal : MedChemComm
Title : Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity.
Year : 2019
Volume : 10
Issue : 7
First Page : 1109
Last Page : 1115
Authors : Reßing N, Marquardt V, Gertzen CGW, Schöler A, Schramm A, Kurz T, Gohlke H, Aigner A, Remke M, Hansen FK.
Abstract : Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A mini library of β-peptoid-capped HDACi was synthesized using a four-step protocol. All compounds were screened in biochemical assays for their inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observed selectivity profile. The synthesized compounds were further examined for tumor cell-inhibitory activity against a panel of neuroblastoma and glioblastoma cell lines. In particular, non-selective compounds with potent activity against HDAC1 and HDAC6 showed strong antiproliferative effects. The most promising HDACi, compound <b>6i</b>, displayed submicromolar tumor cell-inhibitory potential (IC<sub>50</sub>: 0.21-0.67 μM) against all five cancer cell lines investigated and exceeded the activity of the FDA-approved HDACi vorinostat.
|
Inhibition of HDAC6 (unknown origin)
|
Homo sapiens
|
17.9
nM
|
|
Journal : MedChemComm
Title : Design, synthesis and biological evaluation of β-peptoid-capped HDAC inhibitors with anti-neuroblastoma and anti-glioblastoma activity.
Year : 2019
Volume : 10
Issue : 7
First Page : 1109
Last Page : 1115
Authors : Reßing N, Marquardt V, Gertzen CGW, Schöler A, Schramm A, Kurz T, Gohlke H, Aigner A, Remke M, Hansen FK.
Abstract : Histone deacetylases (HDACs) have been identified as promising epigenetic drug targets for the treatment of neuroblastoma and glioblastoma. In this work, we have rationally designed a novel class of peptoid-based histone deacetylase inhibitors (HDACi). A mini library of β-peptoid-capped HDACi was synthesized using a four-step protocol. All compounds were screened in biochemical assays for their inhibition of HDAC1 and HDAC6 and docking studies were performed to rationalize the observed selectivity profile. The synthesized compounds were further examined for tumor cell-inhibitory activity against a panel of neuroblastoma and glioblastoma cell lines. In particular, non-selective compounds with potent activity against HDAC1 and HDAC6 showed strong antiproliferative effects. The most promising HDACi, compound <b>6i</b>, displayed submicromolar tumor cell-inhibitory potential (IC<sub>50</sub>: 0.21-0.67 μM) against all five cancer cell lines investigated and exceeded the activity of the FDA-approved HDACi vorinostat.
|
Inhibition of recombinant human full length C-terminal His/FLAG-tagged HDAC1 expressed in baculovirus infected Sf9 insect cells assessed as decrease in release of 7-amino-4-methoxycoumarin using FTS as substrate preincubated for 10 mins followed by substrate addition measured after 60 sec by microplate reader assay
|
Homo sapiens
|
58.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models.
Year : 2019
Volume : 62
Issue : 18
First Page : 8557
Last Page : 8577
Authors : Shen S, Hadley M, Ustinova K, Pavlicek J, Knox T, Noonepalle S, Tavares MT, Zimprich CA, Zhang G, Robers MB, Bařinka C, Kozikowski AP, Villagra A.
Abstract : Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the <i>Danio rerio</i> HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.
|
Inhibition of recombinant human full length N-terminal GST-tagged HDAC6 expressed in baculovirus infected Sf9 insect cells assessed as decrease in release of 7-amino-4-methoxycoumarin using FTS as substrate preincubated for 10 mins followed by substrate addition measured after 60 sec by microplate reader assay
|
Homo sapiens
|
4.7
nM
|
|
Journal : J Med Chem
Title : Discovery of a New Isoxazole-3-hydroxamate-Based Histone Deacetylase 6 Inhibitor SS-208 with Antitumor Activity in Syngeneic Melanoma Mouse Models.
Year : 2019
Volume : 62
Issue : 18
First Page : 8557
Last Page : 8577
Authors : Shen S, Hadley M, Ustinova K, Pavlicek J, Knox T, Noonepalle S, Tavares MT, Zimprich CA, Zhang G, Robers MB, Bařinka C, Kozikowski AP, Villagra A.
Abstract : Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the <i>Danio rerio</i> HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.
|
Inhibition of recombinant full length human HDAC2 expressed in baculovirus infected Sf9 cells using FAM-RHKK-Ac as substrate incubated for 17 hrs by electrophoretic mobility shift assay
|
Homo sapiens
|
379.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Class I/IIb-Selective HDAC Inhibitor Exhibits Oral Bioavailability and Therapeutic Efficacy in Acute Myeloid Leukemia.
Year : 2020
Volume : 11
Issue : 1
First Page : 56
Last Page : 64
Authors : Shouksmith AE, Gawel JM, Nawar N, Sina D, Raouf YS, Bukhari S, He L, Johns AE, Manaswiyoungkul P, Olaoye OO, Cabral AD, Sedighi A, de Araujo ED, Gunning PT.
Abstract : The HDAC inhibitor 4-<i>tert</i>-butyl-<i>N</i>-(4-(hydroxycarbamoyl)phenyl)benzamide (<b>AES-350</b>, <b>51</b>) was identified as a promising preclinical candidate for the treatment of acute myeloid leukemia (AML), an aggressive malignancy with a meagre 24% 5-year survival rate. Through screening of low-molecular-weight analogues derived from the previously discovered novel HDAC inhibitor, <b>AES-135</b>, compound <b>51</b> demonstrated greater HDAC isoform selectivity, higher cytotoxicity in MV4-11 cells, an improved therapeutic window, and more efficient absorption through cellular and lipid membranes. Compound <b>51</b> also demonstrated improved oral bioavailability compared to SAHA in mouse models. A broad spectrum of experiments, including FACS, ELISA, and Western blotting, were performed to support our hypothesis that <b>51</b> dose-dependently triggers apoptosis in AML cells through HDAC inhibition.
|
Inhibition of tubastatin-Alexa647-tracer binding to recombinant GST-tagged HDAC10 (unknown origin) measured after 1 hr by TR-FRET assay
|
Homo sapiens
|
125.89
nM
|
|
Journal : J Med Chem
Title : Selective Inhibition of Histone Deacetylase 10: Hydrogen Bonding to the Gatekeeper Residue is Implicated.
Year : 2019
Volume : 62
Issue : 9
First Page : 4426
Last Page : 4443
Authors : Géraldy M, Morgen M, Sehr P, Steimbach RR, Moi D, Ridinger J, Oehme I, Witt O, Malz M, Nogueira MS, Koch O, Gunkel N, Miller AK.
Abstract : The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no studies toward selective HDAC10 inhibitors have been published. Using two complementary assays, we found Tubastatin A, an HDAC6 inhibitor, to potently bind HDAC10. We synthesized Tubastatin A derivatives and found that a basic amine in the cap group was required for strong HDAC10 binding. HDAC10 inhibitors mimicked knockdown by causing dose-dependent accumulation of acidic vesicles in a neuroblastoma cell line. Furthermore, docking into human HDAC10 homology models indicated that a hydrogen bond between a cap group nitrogen and the gatekeeper residue Glu272 was responsible for potent HDAC10 binding. Taken together, our data provide an optimal platform for the development of HDAC10-selective inhibitors, as exemplified with the Tubastatin A scaffold.
|
Inhibition of recombinant full length human N-terminal GST-tagged HDAC6 expressed in baculovirus infected sf9 insect cells pretreated with compound followed by Fluor de Lys deacetylase substrate addition by fluorescence method
|
Homo sapiens
|
12.0
nM
|
|
Journal : J Med Chem
Title : Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation.
Year : 2019
Volume : 62
Issue : 23
First Page : 10711
Last Page : 10739
Authors : Vergani B, Sandrone G, Marchini M, Ripamonti C, Cellupica E, Galbiati E, Caprini G, Pavich G, Porro G, Rocchio I, Lattanzio M, Pezzuto M, Skorupska M, Cordella P, Pagani P, Pozzi P, Pomarico R, Modena D, Leoni F, Perego R, Fossati G, Steinkühler C, Stevenazzi A.
Abstract : Histone deacetylase 6 (HDAC6) is a peculiar HDAC isoform whose expression and functional alterations have been correlated with a variety of pathologies such as autoimmune disorders, neurodegenerative diseases, and cancer. It is primarily a cytoplasmic protein, and its deacetylase activity is focused mainly on nonhistone substrates such as tubulin, heat shock protein (HSP)90, Foxp3, and cortactin, to name a few. Selective inhibition of HDAC6 does not show cytotoxic effects in healthy cells, normally associated with the inhibition of Class I HDAC isoforms. Here, we describe the design and synthesis of a new class of potent and selective HDAC6 inhibitors that bear a pentaheterocyclic central core. These compounds show a remarkably low toxicity both in vitro and in vivo and are able to increase the function of regulatory T cells (Tregs) at well-tolerated concentrations, suggesting a potential clinical use for the treatment of degenerative, autoimmune diseases and for organ transplantation.
|
Cytotoxicity against human 697 cells after 48 hrs by CellTiter 96 aqueous one solution assay
|
Homo sapiens
|
201.0
nM
|
|
Journal : J Med Chem
Title : Novel Benzohydroxamate-Based Potent and Selective Histone Deacetylase 6 (HDAC6) Inhibitors Bearing a Pentaheterocyclic Scaffold: Design, Synthesis, and Biological Evaluation.
Year : 2019
Volume : 62
Issue : 23
First Page : 10711
Last Page : 10739
Authors : Vergani B, Sandrone G, Marchini M, Ripamonti C, Cellupica E, Galbiati E, Caprini G, Pavich G, Porro G, Rocchio I, Lattanzio M, Pezzuto M, Skorupska M, Cordella P, Pagani P, Pozzi P, Pomarico R, Modena D, Leoni F, Perego R, Fossati G, Steinkühler C, Stevenazzi A.
Abstract : Histone deacetylase 6 (HDAC6) is a peculiar HDAC isoform whose expression and functional alterations have been correlated with a variety of pathologies such as autoimmune disorders, neurodegenerative diseases, and cancer. It is primarily a cytoplasmic protein, and its deacetylase activity is focused mainly on nonhistone substrates such as tubulin, heat shock protein (HSP)90, Foxp3, and cortactin, to name a few. Selective inhibition of HDAC6 does not show cytotoxic effects in healthy cells, normally associated with the inhibition of Class I HDAC isoforms. Here, we describe the design and synthesis of a new class of potent and selective HDAC6 inhibitors that bear a pentaheterocyclic central core. These compounds show a remarkably low toxicity both in vitro and in vivo and are able to increase the function of regulatory T cells (Tregs) at well-tolerated concentrations, suggesting a potential clinical use for the treatment of degenerative, autoimmune diseases and for organ transplantation.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.33
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-3.643
%
|
|
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
|
0.43
%
|
|
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
|
1.12
%
|
|
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
|
0.43
%
|
|
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
|
1.12
%
|
|
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 HDAC8 (unknown origin) using MAZ-1675 as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs
|
Homo sapiens
|
100.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of potent and selective HDAC6 inhibitors.
Year : 2018
Volume : 143
First Page : 1406
Last Page : 1418
Authors : Wang XX,Wan RZ,Liu ZP
Abstract : Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the modification of histone, HDAC6 targets specific substrates including α-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized.
|
Inhibition of HDAC6 (unknown origin) using FTS as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs
|
Homo sapiens
|
4.7
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of potent and selective HDAC6 inhibitors.
Year : 2018
Volume : 143
First Page : 1406
Last Page : 1418
Authors : Wang XX,Wan RZ,Liu ZP
Abstract : Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the modification of histone, HDAC6 targets specific substrates including α-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized.
|
Inhibition of human HDAC2 expressed in Sf9 insect cells using FTS as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs
|
Homo sapiens
|
48.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of potent and selective HDAC6 inhibitors.
Year : 2018
Volume : 143
First Page : 1406
Last Page : 1418
Authors : Wang XX,Wan RZ,Liu ZP
Abstract : Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the modification of histone, HDAC6 targets specific substrates including α-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized.
|
Inhibition of HDAC1 (unknown origin) using FTS as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs
|
Homo sapiens
|
58.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of potent and selective HDAC6 inhibitors.
Year : 2018
Volume : 143
First Page : 1406
Last Page : 1418
Authors : Wang XX,Wan RZ,Liu ZP
Abstract : Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the modification of histone, HDAC6 targets specific substrates including α-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized.
|
Cytotoxicity against human MV4-11 cells measured after 72 hrs by spectrophotometer method
|
Homo sapiens
|
656.0
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC3 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
14.3
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC6 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
2.59
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC8 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
245.0
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of recombinant full length human HDAC2 expressed in SF9 baculovirus using FAM- labelled acetylated peptide as substrate measured by Electrophoretic mobility shift assay
|
Homo sapiens
|
379.0
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of N-terminal 6 His-SUMO tagged Zebrafish HDAC6 CD2 domain expressed in Escherichia coli BL21(DE3) RILP pretreated for 10 mins before FITC-M344 addition and measured after 10 mins by fluorescence polarization competition assay
|
Danio rerio
|
90.0
nM
|
|
Journal : Eur J Med Chem
Title : PTG-0861: A novel HDAC6-selective inhibitor as a therapeutic strategy in acute myeloid leukaemia.
Year : 2020
Volume : 201
First Page : 112411
Last Page : 112411
Authors : Gawel JM,Shouksmith AE,Raouf YS,Nawar N,Toutah K,Bukhari S,Manaswiyoungkul P,Olaoye OO,Israelian J,Radu TB,Cabral AD,Sina D,Sedighi A,de Araujo ED,Gunning PT
Abstract : Dysregulated Histone Deacetylase (HDAC) activity across multiple human pathologies have highlighted this family of epigenetic enzymes as critical druggable targets, amenable to small molecule intervention. While efficacious, current approaches using non-selective HDAC inhibitors (HDACi) have been shown to cause a range of undesirable clinical toxicities. To circumvent this, recent efforts have focused on the design of highly selective HDACi as a novel therapeutic strategy. Beyond roles in regulating transcription, the unique HDAC6 (with two catalytic domains) regulates the deacetylation of α-tubulin; promoting growth factor-controlled cell motility, cell division, and metastatic hallmarks. Recent studies have linked aberrant HDAC6 function in various hematological cancers including acute myeloid leukaemia and multiple myeloma. Herein, we report the discovery, in vitro characterization, and biological evaluation of PTG-0861 (JG-265), a novel HDAC6-selective inhibitor with strong isozyme-selectivity (∼36× ) and low nanomolar potency (IC = 5.92 nM) against HDAC6. This selectivity profile was rationalized via in silico docking studies and also observed in cellulo through cellular target engagement. Moreover, PTG-0861 achieved relevant potency against several blood cancer cell lines (e.g. MV4-11, MM1S), whilst showing limited cytotoxicity against non-malignant cells (e.g. NHF, HUVEC) and CD-1 mice. In examining compound stability and cellular permeability, PTG-0861 revealed a promising in vitro pharmacokinetic (PK) profile. Altogether, in this study we identified a novel and potent HDAC6-selective inhibitor (∼4× more selective than current clinical standards - citarinostat, ricolinostat), which achieves cellular target engagement, efficacy in hematological cancer cells with a promising safety profile and in vitro PK.
|
Inhibition of human HDAC6 (unknown origin) using RHKKAc as substrate by fluorescence method
|
Homo sapiens
|
27.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma.
Year : 2021
Volume : 34
First Page : 127763
Last Page : 127763
Authors : Naveen Sadhu M,Sivanandhan D,Gajendran C,Tantry S,Dewang P,Murugan K,Chickamunivenkatappa S,Zainuddin M,Nair S,Vaithilingam K,Rajagopal S
Abstract : Lysine specific demethylase 1 (LSD1) and HDAC6 are epigenetic proteins associated with several diseases, including cancer and combined inhibition of these proteins could be highly beneficial in treating some cancers such as AML, MM and solid tumors. Multiple myeloma (MM) is a challenging cancer with fast relapse rate where novel treatment options are the need of the hour. We have designed and developed novel, LSD1 and HDAC6 selective dual inhibitors to target MM. Our dual inhibitor compound 1 shows superior potency in multiple MM cell lines. In MM.1S xenograft model compound 1 shows superior efficacy compared to single agent LSD1 and HDAC6 inhibitors by oral administration and is well tolerated. Further evaluation of the molecule in other cancers is in progress.
|
Antiproliferative activity against human MM1.S cells assessed as reduction in cell viability after 144 hrs
|
Homo sapiens
|
0.85
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma.
Year : 2021
Volume : 34
First Page : 127763
Last Page : 127763
Authors : Naveen Sadhu M,Sivanandhan D,Gajendran C,Tantry S,Dewang P,Murugan K,Chickamunivenkatappa S,Zainuddin M,Nair S,Vaithilingam K,Rajagopal S
Abstract : Lysine specific demethylase 1 (LSD1) and HDAC6 are epigenetic proteins associated with several diseases, including cancer and combined inhibition of these proteins could be highly beneficial in treating some cancers such as AML, MM and solid tumors. Multiple myeloma (MM) is a challenging cancer with fast relapse rate where novel treatment options are the need of the hour. We have designed and developed novel, LSD1 and HDAC6 selective dual inhibitors to target MM. Our dual inhibitor compound 1 shows superior potency in multiple MM cell lines. In MM.1S xenograft model compound 1 shows superior efficacy compared to single agent LSD1 and HDAC6 inhibitors by oral administration and is well tolerated. Further evaluation of the molecule in other cancers is in progress.
|
Inhibition of human recombinant HDAC1 using ZMAL (Z-Lys(Ac)-AMC) fluorogenic substrate incubated for 90 mins by fluorescence based assay
|
Homo sapiens
|
190.0
nM
|
|
Journal : J Med Chem
Title : Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups.
Year : 2020
Volume : 63
Issue : 18
First Page : 10339
Last Page : 10351
Authors : Reßing N,Sönnichsen M,Osko JD,Schöler A,Schliehe-Diecks J,Skerhut A,Borkhardt A,Hauer J,Kassack MU,Christianson DW,Bhatia S,Hansen FK
Abstract : Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.
|
Inhibition of human recombinant HDAC6 using ZMAL (Z-Lys(Ac)-AMC) fluorogenic substrate incubated for 90 mins by fluorescence based assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : J Med Chem
Title : Multicomponent Synthesis, Binding Mode, and Structure-Activity Relationship of Selective Histone Deacetylase 6 (HDAC6) Inhibitors with Bifurcated Capping Groups.
Year : 2020
Volume : 63
Issue : 18
First Page : 10339
Last Page : 10351
Authors : Reßing N,Sönnichsen M,Osko JD,Schöler A,Schliehe-Diecks J,Skerhut A,Borkhardt A,Hauer J,Kassack MU,Christianson DW,Bhatia S,Hansen FK
Abstract : Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by investigating the inhibition of recombinant HDAC enzymes and protein acetylation. A cocrystal structure of HDAC6 complexed with NR-160 disclosed that the steric complementarity of the bifurcated capping group of NR-160 to the L1 and L2 loop pockets may be responsible for its HDAC6-selective inhibition. While NR-160 displayed only low cytotoxicity as a single agent against leukemia cell lines, it augmented the apoptosis induction of the proteasome inhibitor bortezomib in combination experiments significantly. Furthermore, a combinatorial high-throughput drug screen revealed significantly enhanced cytotoxicity when NR-160 was used in combination with epirubicin and daunorubicin. The synergistic effect in combination with bortezomib and anthracyclines highlights the potential of NR-160 in combination therapies.
|
Inhibition of HDAC1 (unknown origin) using FTS as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs and measured over 30 mins
|
Homo sapiens
|
58.0
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 HDAC2 expressed in Sf9 cells using FTS as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs and measured over 30 mins
|
Homo sapiens
|
48.0
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 His-tagged HDAC3 (1 to 428 residues)/human N-terminal GST-tagged NcoR2 (395 to 489 residues) expressed in sf9 cells using FTS as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs and measured over 30 mins
|
Homo sapiens
|
51.0
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 HDAC6 (unknown origin) using FTS as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs and measured over 30 mins
|
Homo sapiens
|
5.0
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of HDAC8 (unknown origin) using MAZ-1675 as substrate preincubated for 10 mins followed by substrate addition and shaken for 60 secs and measured over 30 mins
|
Homo sapiens
|
100.0
nM
|
|
Journal : J Med Chem
Title : Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight.
Year : 2020
Volume : 63
Issue : 21.0
First Page : 12460
Last Page : 12484
Authors : Ho TCS,Chan AHY,Ganesan A
Abstract : It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development for oncology as well as other therapeutic indications. This Perspective reviews the biological and medicinal chemistry advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
|
Inhibition of human HDAC6 preincubated for 15 mins followed by substrate addition by fluorescence-based assay
|
Homo sapiens
|
6.8
nM
|
|
|
Inhibition of human HDAC1 preincubated for 15 mins followed by substrate addition by fluorescence-based assay
|
Homo sapiens
|
19.0
nM
|
|
|
Inhibition of Class 1/2b HDAC in human HL-60 cells by HDAC-Glo assay
|
Homo sapiens
|
902.0
nM
|
|
|
Inhibition of HDAC1 (unknown origin)
|
Homo sapiens
|
58.0
nM
|
|
|
Inhibition of HDAC2 (unknown origin)
|
Homo sapiens
|
48.0
nM
|
|
|
Inhibition of HDAC3 (unknown origin)
|
Homo sapiens
|
51.0
nM
|
|
|
Inhibition of HDAC6 (unknown origin)
|
Homo sapiens
|
4.7
nM
|
|
|
Inhibition of HDAC8 (unknown origin)
|
Homo sapiens
|
100.0
nM
|
|
|
Inhibition of recombinant HDAC3 (unknown origin) using Boc-Lys(acetyl)-AMC as substrate preincubated for 1 hr followed by substrate addition and measured after 2 hrs by fluorescence based assay
|
Homo sapiens
|
51.0
nM
|
|
|
Inhibition of recombinant HDAC6 (unknown origin) using Boc-Lys(acetyl)-AMC as substrate preincubated for 1 hr followed by substrate addition and measured after 2 hrs by fluorescence based assay
|
Homo sapiens
|
4.7
nM
|
|
|
Inhibition of HDAC3 (unknown origin) using FTS as substrate preincubated for 10 mins followed by substrate and trypsin addition by microplate reader based assay
|
Homo sapiens
|
51.0
nM
|
|
|
Inhibition of HDAC6 (unknown origin) using FTS as substrate preincubated for 10 mins followed by substrate and trypsin addition by microplate reader based assay
|
Homo sapiens
|
4.7
nM
|
|
