|
Displacement of FAM-labeled ZBA248 from BRD4 BD1 (44 to 168 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
25.5
nM
|
|
Displacement of FAM-labeled ZBA248 from BRD4 BD1 (44 to 168 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
10.9
nM
|
|
Journal : J. Med. Chem.
Title : Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.
Year : 2015
Volume : 58
Issue : 12
First Page : 4927
Last Page : 4939
Authors : Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S.
Abstract : Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.
|
Displacement of FAM-labeled ZBA248 from BRD4 BD2 (333 to 460 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
16.6
nM
|
|
Displacement of FAM-labeled ZBA248 from BRD4 BD2 (333 to 460 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.
Year : 2015
Volume : 58
Issue : 12
First Page : 4927
Last Page : 4939
Authors : Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S.
Abstract : Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.
|
Displacement of FAM-labeled ZBA248 from BRD2 BD1 (72 to 205 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
16.6
nM
|
|
Journal : J. Med. Chem.
Title : Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.
Year : 2015
Volume : 58
Issue : 12
First Page : 4927
Last Page : 4939
Authors : Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S.
Abstract : Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.
|
Displacement of FAM-labeled ZBA248 from BRD2 BD2 (349 to 460 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
5.4
nM
|
|
Journal : J. Med. Chem.
Title : Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.
Year : 2015
Volume : 58
Issue : 12
First Page : 4927
Last Page : 4939
Authors : Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S.
Abstract : Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.
|
Displacement of FAM-labeled ZBA248 from BRD3 BD1 (24 to 144 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
10.7
nM
|
|
Journal : J. Med. Chem.
Title : Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.
Year : 2015
Volume : 58
Issue : 12
First Page : 4927
Last Page : 4939
Authors : Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S.
Abstract : Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.
|
Displacement of FAM-labeled ZBA248 from BRD3 BD2 (306 to 417 amino acid residues) (unknown origin) expressed in Rosetta2 DE3 cells after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-Based Design of γ-Carboline Analogues as Potent and Specific BET Bromodomain Inhibitors.
Year : 2015
Volume : 58
Issue : 12
First Page : 4927
Last Page : 4939
Authors : Ran X, Zhao Y, Liu L, Bai L, Yang CY, Zhou B, Meagher JL, Chinnaswamy K, Stuckey JA, Wang S.
Abstract : Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the treatment of human cancers and other diseases and conditions. In this paper, we report the design, synthesis, and evaluation of γ-carboline-containing compounds as a new class of small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates high selectivity over other non-BET bromodomain-containing proteins. Compound 18 potently and selectively inhibits cell growth in human acute leukemia cell lines harboring the rearranged mixed lineage leukemia 1 gene. We have determined a cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which provides a solid structural basis for the compound's high binding affinity and for its further structure-based optimization. Compound 18 represents a promising lead compound for the development of a new class of therapeutics for the treatment of human cancer and other conditions.
|
Inhibition of BRD4 bromodomain 1 (unknown origin)
|
Homo sapiens
|
20.0
nM
|
|
Journal : J. Med. Chem.
Title : Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors.
Year : 2016
Volume : 59
Issue : 4
First Page : 1271
Last Page : 1298
Authors : Romero FA, Taylor AM, Crawford TD, Tsui V, Côté A, Magnuson S.
Abstract : Bromodomains, small protein modules that recognize acetylated lysine on histones, play a significant role in the epigenome, where they function as "readers" that ultimately determine the functional outcome of the post-translational modification. Because the initial discovery of selective BET inhibitors have helped define the role of that protein family in oncology and inflammation, BET bromodomains have continued to garner the most attention of any other bromodomain. More recently, non-BET bromodomain inhibitors that are potent and selective have been disclosed for ATAD2, CBP, BRD7/9, BRPF, BRPF/TRIM24, CECR2, SMARCA4, and BAZ2A/B. Such novel inhibitors can be used to probe the physiological function of these non-BET bromodomains and further understanding of their role in certain disease states. Here, we provide an update to the progress in identifying selective bromodomain inhibitors and their use as biological tools, as well as our perspective on the field.
|
Inhibition of acetylated H4 binding to BRD4 (unknown origin)
|
Homo sapiens
|
92.0
nM
|
|
Journal : J Med Chem
Title : Drug Discovery Targeting Bromodomain-Containing Protein 4.
Year : 2017
Volume : 60
Issue : 11
First Page : 4533
Last Page : 4558
Authors : Liu Z, Wang P, Chen H, Wold EA, Tian B, Brasier AR, Zhou J.
Abstract : BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein-protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted.
|
Inhibition of acetylated H4 binding to BRD2 (unknown origin)
|
Homo sapiens
|
92.0
nM
|
|
Journal : J Med Chem
Title : Drug Discovery Targeting Bromodomain-Containing Protein 4.
Year : 2017
Volume : 60
Issue : 11
First Page : 4533
Last Page : 4558
Authors : Liu Z, Wang P, Chen H, Wold EA, Tian B, Brasier AR, Zhou J.
Abstract : BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein-protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted.
|
Inhibition of acetylated H4 binding to BRD3 (unknown origin)
|
Homo sapiens
|
92.0
nM
|
|
Journal : J Med Chem
Title : Drug Discovery Targeting Bromodomain-Containing Protein 4.
Year : 2017
Volume : 60
Issue : 11
First Page : 4533
Last Page : 4558
Authors : Liu Z, Wang P, Chen H, Wold EA, Tian B, Brasier AR, Zhou J.
Abstract : BRD4, the most extensively studied member of the BET family, is an epigenetic regulator that localizes to DNA via binding to acetylated histones and controls the expression of therapeutically important gene regulatory networks through the recruitment of transcription factors to form mediator complexes, phosphorylating RNA polymerase II, and by its intrinsic histone acetyltransferase activity. Disrupting the protein-protein interactions between BRD4 and acetyl-lysine has been shown to effectively block cell proliferation in cancer, cytokine production in acute inflammation, and so forth. To date, significant efforts have been devoted to the development of BRD4 inhibitors, and consequently, a dozen have progressed to human clinical trials. Herein, we summarize the advances in drug discovery and development of BRD4 inhibitors by focusing on their chemotypes, in vitro and in vivo activity, selectivity, relevant mechanisms of action, and therapeutic potential. Opportunities and challenges to achieve selective and efficacious BRD4 inhibitors as a viable therapeutic strategy for human diseases are also highlighted.
|
Inhibition of BRD4 BD1-BD2 (unknown origin) using tetraacetylated histone peptide as substrate after 2 hrs by alphascreen assay
|
Homo sapiens
|
16.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment.
Year : 2017
Volume : 27
Issue : 20
First Page : 4606
Last Page : 4613
Authors : Ali I, Lee J, Go A, Choi G, Lee K.
Abstract : Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay. The substantial antiproliferative activities in human cancer cell lines, promising drug-like properties, and the selectivity for the BET family make the lead compound (13) as a novel BRD4 inhibitor motif for anti-cancer drug discovery.
|
Antiproliferative activity against human TY82 cells
|
Homo sapiens
|
67.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment.
Year : 2017
Volume : 27
Issue : 20
First Page : 4606
Last Page : 4613
Authors : Ali I, Lee J, Go A, Choi G, Lee K.
Abstract : Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay. The substantial antiproliferative activities in human cancer cell lines, promising drug-like properties, and the selectivity for the BET family make the lead compound (13) as a novel BRD4 inhibitor motif for anti-cancer drug discovery.
|
Antiproliferative activity against human THP1 cells
|
Homo sapiens
|
33.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery of novel [1,2,4]triazolo[4,3-a]quinoxaline aminophenyl derivatives as BET inhibitors for cancer treatment.
Year : 2017
Volume : 27
Issue : 20
First Page : 4606
Last Page : 4613
Authors : Ali I, Lee J, Go A, Choi G, Lee K.
Abstract : Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay. The substantial antiproliferative activities in human cancer cell lines, promising drug-like properties, and the selectivity for the BET family make the lead compound (13) as a novel BRD4 inhibitor motif for anti-cancer drug discovery.
|
Inhibition of BRD4 bromodomain-1 (unknown origin) by AlphaScreen assay
|
Homo sapiens
|
92.0
nM
|
|
Journal : Eur J Med Chem
Title : Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer.
Year : 2018
Volume : 152
First Page : 542
Last Page : 559
Authors : Xue X, Zhang Y, Wang C, Zhang M, Xiang Q, Wang J, Wang A, Li C, Zhang C, Zou L, Wang R, Wu S, Lu Y, Chen H, Ding K, Li G, Xu Y.
Abstract : The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
|
Antiproliferative activity against human LNCAP cells
|
Homo sapiens
|
111.4
nM
|
|
Journal : Eur J Med Chem
Title : Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer.
Year : 2018
Volume : 152
First Page : 542
Last Page : 559
Authors : Xue X, Zhang Y, Wang C, Zhang M, Xiang Q, Wang J, Wang A, Li C, Zhang C, Zou L, Wang R, Wu S, Lu Y, Chen H, Ding K, Li G, Xu Y.
Abstract : The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD2 bromodomain 1 (72 to 205 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
16.6
nM
|
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD2 bromodomain 1 (72 to 205 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
33.3
nM
|
|
Journal : J Med Chem
Title : Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
Year : 2018
Volume : 61
Issue : 2
First Page : 462
Last Page : 481
Authors : Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, Lin M, Liu L, Yang CY, Zhao Y, McEachern D, Przybranowski S, Wen B, Sun D, Wang S.
Abstract : The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD2 bromodomain 2 (349 to 460 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
5.4
nM
|
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD2 bromodomain 2 (349 to 460 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
24.8
nM
|
|
Journal : J Med Chem
Title : Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
Year : 2018
Volume : 61
Issue : 2
First Page : 462
Last Page : 481
Authors : Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, Lin M, Liu L, Yang CY, Zhao Y, McEachern D, Przybranowski S, Wen B, Sun D, Wang S.
Abstract : The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD3 bromodomain 1 (24 to 144 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
10.7
nM
|
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD3 bromodomain 1 (24 to 144 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
38.5
nM
|
|
Journal : J Med Chem
Title : Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
Year : 2018
Volume : 61
Issue : 2
First Page : 462
Last Page : 481
Authors : Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, Lin M, Liu L, Yang CY, Zhao Y, McEachern D, Przybranowski S, Wen B, Sun D, Wang S.
Abstract : The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD3 bromodomain 2 (306 to 417residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
4.0
nM
|
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD3 bromodomain 2 (306 to 417residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
21.0
nM
|
|
Journal : J Med Chem
Title : Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
Year : 2018
Volume : 61
Issue : 2
First Page : 462
Last Page : 481
Authors : Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, Lin M, Liu L, Yang CY, Zhao Y, McEachern D, Przybranowski S, Wen B, Sun D, Wang S.
Abstract : The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD4 bromodomain 1 (44 to 168 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
25.5
nM
|
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD4 bromodomain 1 (44 to 168 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
10.9
nM
|
|
Journal : J Med Chem
Title : Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
Year : 2018
Volume : 61
Issue : 2
First Page : 462
Last Page : 481
Authors : Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, Lin M, Liu L, Yang CY, Zhao Y, McEachern D, Przybranowski S, Wen B, Sun D, Wang S.
Abstract : The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD4 bromodomain 2 (333 to 460 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
6.0
nM
|
|
Inhibition of FAM-labeled ZBA248 binding to recombinant N-terminal His6-tagged BRD4 bromodomain 2 (333 to 460 residues) (unknown origin) expressed in Escherichia coli Rosetta2 DE3 after 30 mins by fluorescence polarization assay
|
Homo sapiens
|
16.6
nM
|
|
Journal : J Med Chem
Title : Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression.
Year : 2018
Volume : 61
Issue : 2
First Page : 462
Last Page : 481
Authors : Zhou B, Hu J, Xu F, Chen Z, Bai L, Fernandez-Salas E, Lin M, Liu L, Yang CY, Zhao Y, McEachern D, Przybranowski S, Wen B, Sun D, Wang S.
Abstract : The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, and testis-specific BRDT members, are epigenetic "readers" and play a key role in the regulation of gene transcription. BET proteins are considered to be attractive therapeutic targets for cancer and other human diseases. Recently, heterobifunctional small-molecule BET degraders have been designed based upon the proteolysis targeting chimera (PROTAC) concept to induce BET protein degradation. Herein, we present our design, synthesis, and evaluation of a new class of PROTAC BET degraders. One of the most promising compounds, 23, effectively degrades BRD4 protein at concentrations as low as 30 pM in the RS4;11 leukemia cell line, achieves an IC50 value of 51 pM in inhibition of RS4;11 cell growth and induces rapid tumor regression in vivo against RS4;11 xenograft tumors. These data establish that compound 23 (BETd-260/ZBC260) is a highly potent and efficacious BET degrader.
|
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
|
-2.34
%
|
|
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 recombinant full length human N-terminal His6-tagged BRD4 (2 to 1362 residues) expressed in baculovirus infected insect cells using histone H4 peptide as substrate by alpha screen assay
|
Homo sapiens
|
92.0
nM
|
|
Journal : Eur J Med Chem
Title : Rational design of 5-((1H-imidazol-1-yl)methyl)quinolin-8-ol derivatives as novel bromodomain-containing protein 4 inhibitors.
Year : 2019
Volume : 163
First Page : 281
Last Page : 294
Authors : Xing J, Zhang R, Jiang X, Hu T, Wang X, Qiao G, Wang J, Yang F, Luo X, Chen K, Shen J, Luo C, Jiang H, Zheng M.
Abstract : Bromodomain-containing protein 4 (BRD4), an epigenetic reader of acetyl lysine, has emerged as a promising therapeutic target for many diseases including cancer, inflammation and heart failure. Our previous study reported that nitroxoline, an FDA approved antibiotic, showed potential BRD4 inhibitory activity and antiproliferation activity against leukemia cell lines. In this study, we further explored the structure-activity relationship (SAR) around nitroxoline and employed our previously developed machine learning based activity scoring function BRD4LGR for further analysis. To improve the cellular level activity, physico-chemical properties were optimized using computational approaches. Then the candidates were tested for their ADME/T profiles. Finally, based on this rational hit-to-lead optimization strategy, 3 drug-like BRD4 inhibitors were obtained, with different profiles on cell line selectivity for multiple myeloma, leukemia and triple negative breast cancer. Further mechanism study showed these compounds could down-regulate c-Myc to inhibit cancer cell growth. This work illustrates the application of multiple computer-aided drug design techniques in a hit-to-lead optimization scenario, and provides novel potent BRD4 inhibitors with different phenotype propensities for future cancer treatment.
|
Antiproliferative activity against human MV4-11 cells assessed as cell growth inhibition after 4 days by CCK8 assay
|
Homo sapiens
|
17.6
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Year : 2019
Volume : 182
First Page : 111633
Last Page : 111633
Authors : Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y.
Abstract : Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
|
Binding affinity to human recombinant BRD4 BD1 (44 to 168 residues) by fluorescence polarization assay
|
Homo sapiens
|
11.7
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Year : 2019
Volume : 182
First Page : 111633
Last Page : 111633
Authors : Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y.
Abstract : Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
|
Binding affinity to human recombinant BRD4 BD2 (333 to 460 residues) by fluorescence polarization assay
|
Homo sapiens
|
9.9
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Year : 2019
Volume : 182
First Page : 111633
Last Page : 111633
Authors : Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y.
Abstract : Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
|
Binding affinity to human recombinant BRD3 BD1 (24 to 144 residues) by fluorescence polarization assay
|
Homo sapiens
|
8.7
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Year : 2019
Volume : 182
First Page : 111633
Last Page : 111633
Authors : Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y.
Abstract : Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
|
Binding affinity to human recombinant BRD3 BD2 (306 to 417 residues) by fluorescence polarization assay
|
Homo sapiens
|
11.2
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Year : 2019
Volume : 182
First Page : 111633
Last Page : 111633
Authors : Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y.
Abstract : Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
|
Binding affinity to human recombinant BRD2 BD1 (72 to 205 residues) by fluorescence polarization assay
|
Homo sapiens
|
33.2
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Year : 2019
Volume : 182
First Page : 111633
Last Page : 111633
Authors : Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y.
Abstract : Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
|
Binding affinity to human recombinant BRD2 BD2 (349 to 460 residues) by fluorescence polarization assay
|
Homo sapiens
|
10.3
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Year : 2019
Volume : 182
First Page : 111633
Last Page : 111633
Authors : Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y.
Abstract : Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
|
Antiproliferative activity against human MM1S cells assessed as cell growth inhibition after 4 days by CCK8 assay
|
Homo sapiens
|
22.7
nM
|
|
Journal : Eur J Med Chem
Title : Discovery, structural insight, and bioactivities of BY27 as a selective inhibitor of the second bromodomains of BET proteins.
Year : 2019
Volume : 182
First Page : 111633
Last Page : 111633
Authors : Chen D, Lu T, Yan Z, Lu W, Zhou F, Lyu X, Xu B, Jiang H, Chen K, Luo C, Zhao Y.
Abstract : Recently, selective inhibition of BET BD2 is emerging as a promising strategy for drug discovery. Despite significant progress in this area, systematic studies of selective BET BD2 inhibitors are still few. In this study, we report the discovery of a potent and selective BET BD2 inhibitor BY27 (47). Our high resolution co-crystal structures of 47/BRD2 BD1 and BD2 showed that the triazole group of 47, water molecules, H433 and N429 in BRD2 BD2 established a water-bridged H-bonding network, which is responsible for the observed selectivities. DNA microarray analysis of HepG2 cells treated with 47 or OTX015 demonstrated the transcriptome impact differences between a BET BD2 selective inhibitor and a pan BET inhibitor. In a MV4-11 mouse xenograft model, 47 caused 67% of tumor growth inhibition and was less toxic than a pan BET inhibitor 1 at high doses. We conclude that the improved safety profile of selective BET BD2 inhibitors warrant future studies in BET associated diseases.
|
Binding affinity to human BRD4 BD1 (44 to 168 residues) by fluorescence polarization assay
|
Homo sapiens
|
23.0
nM
|
|
Binding affinity to human BRD4 BD1 (44 to 168 residues) by fluorescence polarization assay
|
Homo sapiens
|
5.7
nM
|
|
Journal : J Med Chem
Title : Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression.
Year : 2018
Volume : 61
Issue : 15
First Page : 6685
Last Page : 6704
Authors : Qin C, Hu Y, Zhou B, Fernandez-Salas E, Yang CY, Liu L, McEachern D, Przybranowski S, Wang M, Stuckey J, Meagher J, Bai L, Chen Z, Lin M, Yang J, Ziazadeh DN, Xu F, Hu J, Xiang W, Huang L, Li S, Wen B, Sun D, Wang S.
Abstract : Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.
|
Inhibition of BRD4 (unknown origin)
|
Homo sapiens
|
92.0
nM
|
|
Journal : J Med Chem
Title : Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors.
Year : 2020
Volume : 63
Issue : 8
First Page : 3956
Last Page : 3975
Authors : Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, Jiang H, Chen S, Luo C, Zhou B.
Abstract : The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
|
Inhibition of SGRG-K(Ac)-GG-K(Ac)-GLG-K(Ac)-GGA-K(Ac)-RHRKVGG-K-Biotin binding to N-terminal His6-tagged BRD4 bromodomain 1 (49 to 170 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) preincubated for 15 mins followed by biotin-labeled H4 peptide addition and measured after 10 mins by Alphascreen assay
|
Homo sapiens
|
40.8
nM
|
|
Journal : J Med Chem
Title : Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors.
Year : 2020
Volume : 63
Issue : 8
First Page : 3956
Last Page : 3975
Authors : Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, Jiang H, Chen S, Luo C, Zhou B.
Abstract : The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
|
Inhibition of SGRG-K(Ac)-GG-K(Ac)-GLG-K(Ac)-GGA-K(Ac)-RHRKVGG-K-Biotin binding to N-terminal His6-tagged BRD4 bromodomain 2 (344 to 455 residues) (unknown origin) expressed in Escherichia coli BL21 (DE3) preincubated for 15 mins followed by biotin-labeled H4 peptide addition and measured after 10 mins by Alphascreen assay
|
Homo sapiens
|
197.0
nM
|
|
Journal : J Med Chem
Title : Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors.
Year : 2020
Volume : 63
Issue : 8
First Page : 3956
Last Page : 3975
Authors : Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, Jiang H, Chen S, Luo C, Zhou B.
Abstract : The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
|
Antiproliferative activity against human MV4-11 cells assessed as reduction in cell viability measured after 72 hrs by Celltitre-glo luminescence assay
|
Homo sapiens
|
46.3
nM
|
|
Journal : J Med Chem
Title : Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors.
Year : 2020
Volume : 63
Issue : 8
First Page : 3956
Last Page : 3975
Authors : Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, Jiang H, Chen S, Luo C, Zhou B.
Abstract : The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
|
Antiproliferative activity against human Kasumi-1 cells assessed as reduction in cell viability measured after 72 hrs by Celltitre-glo luminescence assay
|
Homo sapiens
|
135.0
nM
|
|
Journal : J Med Chem
Title : Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors.
Year : 2020
Volume : 63
Issue : 8
First Page : 3956
Last Page : 3975
Authors : Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, Jiang H, Chen S, Luo C, Zhou B.
Abstract : The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
|
Antiproliferative activity against human RS4:11 cells assessed as reduction in cell viability measured after 72 hrs by Celltitre-glo luminescence assay
|
Homo sapiens
|
416.0
nM
|
|
Journal : J Med Chem
Title : Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors.
Year : 2020
Volume : 63
Issue : 8
First Page : 3956
Last Page : 3975
Authors : Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, Jiang H, Chen S, Luo C, Zhou B.
Abstract : The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
|
Antiproliferative activity against human MM1S cells assessed as reduction in cell viability measured after 72 hrs by Celltitre-glo luminescence assay
|
Homo sapiens
|
137.0
nM
|
|
Journal : J Med Chem
Title : Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors.
Year : 2020
Volume : 63
Issue : 8
First Page : 3956
Last Page : 3975
Authors : Li Z, Xiao S, Yang Y, Chen C, Lu T, Chen Z, Jiang H, Chen S, Luo C, Zhou B.
Abstract : The bromodomain and extra-terminal (BET) family proteins have recently emerged as promising drug targets for cancer therapy. In this study, identification of an 8-methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one fragment (47) as a new binder to the BET bromodomains and the subsequent incorporation of fragment 47 to the scaffold of ABBV-075, which recently entered Phase I clinical trials, enabled the generation of a series of highly potent BET bromodomain inhibitors. Further druggability optimization led to the discovery of compound 38 as a potential preclinical candidate. Significantly, compared with ABBV-075, which exhibits a 63-fold selectivity for BRD4(1) over EP300, compound 38 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300. Orally administered 38 achieves a complete inhibition of tumor growth with a tumor growth inhibition (TGI) of 99.7% accompanied by good tolerability.
|
Displacement of 5-FITC labelled (+)-JQ1 from His6-tagged human BRD4 bromodomain 1 expressed in Escherichia coli BL21(DE3) )-codon plus-RIL cells incubated for 4 hrs in dark condition by fluorescence anisotropy binding assay
|
Homo sapiens
|
34.3
nM
|
|
Journal : J Med Chem
Title : Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors.
Year : 2019
Volume : 62
Issue : 18
First Page : 8642
Last Page : 8663
Authors : Hu J, Tian CQ, Damaneh MS, Li Y, Cao D, Lv K, Yu T, Meng T, Chen D, Wang X, Chen L, Li J, Song SS, Huan XJ, Qin L, Shen J, Wang YQ, Miao ZH, Xiong B.
Abstract : BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound <b>4</b> harboring a five-membered-ring linker motif, we quickly identified lead compound <b>7</b>, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1<i>H</i>)-one structure. Among them, compound <b>19</b> was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound <b>19</b> is a potential BET protein drug candidate for the treatment of cancer.
|
Antiproliferative activity against human MM1S cells after 72 hrs by CCK8 or SRB assay
|
Homo sapiens
|
6.3
nM
|
|
Journal : J Med Chem
Title : Structure-Based Discovery and Development of a Series of Potent and Selective Bromodomain and Extra-Terminal Protein Inhibitors.
Year : 2019
Volume : 62
Issue : 18
First Page : 8642
Last Page : 8663
Authors : Hu J, Tian CQ, Damaneh MS, Li Y, Cao D, Lv K, Yu T, Meng T, Chen D, Wang X, Chen L, Li J, Song SS, Huan XJ, Qin L, Shen J, Wang YQ, Miao ZH, Xiong B.
Abstract : BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound <b>4</b> harboring a five-membered-ring linker motif, we quickly identified lead compound <b>7</b>, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1<i>H</i>)-one structure. Among them, compound <b>19</b> was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound <b>19</b> is a potential BET protein drug candidate for the treatment of cancer.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
22.08
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-1.965
%
|
|
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
|
0.49
%
|
|
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
|
4.23
%
|
|
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
|
4.23
%
|
|
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
|
0.49
%
|
|
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 His-tagged BRD4 bromodomain 1 (unknown origin) using [Lys (5,8,12,16) Ac] H4(1-21) as substrate by fluorescence based assay
|
Homo sapiens
|
9.2
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes.
Year : 2021
Volume : 209
First Page : 112868
Last Page : 112868
Authors : Chen J,Li Y,Zhang J,Zhang M,Wei A,Liu H,Xie Z,Ren W,Duan W,Zhang Z,Shen A,Hu Y
Abstract : According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines.
|
Inhibition of His-tagged BRD4 bromodomain 2 (unknown origin) using [Lys (5,8,12,16) Ac] H4(1-21) as substrate by fluorescence based assay
|
Homo sapiens
|
15.4
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes.
Year : 2021
Volume : 209
First Page : 112868
Last Page : 112868
Authors : Chen J,Li Y,Zhang J,Zhang M,Wei A,Liu H,Xie Z,Ren W,Duan W,Zhang Z,Shen A,Hu Y
Abstract : According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines.
|
Antiproliferative activity against human MV4-11 cells assessed as cell viability after 72 hrs by CCK8 assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of selective HDAC/BRD4 dual inhibitors as epigenetic probes.
Year : 2021
Volume : 209
First Page : 112868
Last Page : 112868
Authors : Chen J,Li Y,Zhang J,Zhang M,Wei A,Liu H,Xie Z,Ren W,Duan W,Zhang Z,Shen A,Hu Y
Abstract : According to the binding mode of ABBV-744 with bromodomains and the cape space of HDAC, the novel selective HDAC/BRD4 dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. Evaluating the biomolecular activities through SARs exploration identified three kinds of selective dual inhibitors 41c (HDAC1/BRD4), 43a (pan-HDAC/BRD4) and 43d (HDAC6/BRD4(BD2)), whose target-related cellular activities in MV-4-11 cells were also confirmed. Significantly, the selective dual inhibitor 41c (HDAC1/BRD4) exhibited synergistic effects against MV-4-11 cells, which strongly induced G0/G1 cell cycle arrest and apoptosis, and the first HDAC6/BRD4(BD2) dual inhibitor was found. This study provides support for selective HDAC/BRD4 dual inhibitors as epigenetic probes based on pyrrolopyridone core for the future biological evaluation in different cancer cell lines.
|
Cytotoxicity against human MOLM-14 cells assessed as reduction in cell viability incubated for 72 hrs
|
Homo sapiens
|
80.0
nM
|
|
|
Anticancer activity against human HL-60 cells assessed as cell growth inhibition by CellTiter-Glo luminescent assay
|
Homo sapiens
|
820.0
nM
|
|
