|
Inhibition of SARS coronavirus-induced cytopathogenicity in Vero E6 cells at 20 uM
|
SARS coronavirus
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus.
Year : 2007
Volume : 50
Issue : 17
First Page : 4087
Last Page : 4095
Authors : Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS.
Abstract : In this study, 221 phytocompounds were evaluated for activity against anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) activities using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Ten diterpenoids (1-10), two sesquiterpenoids (11 and 12), two triterpenoids (13 and 14), five lignoids (15-19), curcumin (20), and reference controls niclosamide (21) and valinomycin (22) were potent inhibitors at concentrations between 3.3 and 10 microM. The concentrations of the 22 compounds to inhibit 50% of Vero E6 cell proliferation (CC50) and viral replication (EC50) were measured. The selective index values (SI = CC50/EC50) of the most potent compounds 1, 5, 6, 8, 14, and 16 were 58, >510, 111, 193, 180, and >667, respectively. Betulinic acid (13) and savinin (16) were competitive inhibitors of SARS-CoV 3CL protease with Ki values = 8.2 +/- 0.7 and 9.1 +/- 2.4 microM, respectively. Our findings suggest that specific abietane-type diterpenoids and lignoids exhibit strong anti-SARS-CoV effects.
|
Inhibition of SARS coronavirus-induced cytopathogenicity in Vero E6 cells at 10 uM
|
SARS coronavirus
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus.
Year : 2007
Volume : 50
Issue : 17
First Page : 4087
Last Page : 4095
Authors : Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS.
Abstract : In this study, 221 phytocompounds were evaluated for activity against anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) activities using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Ten diterpenoids (1-10), two sesquiterpenoids (11 and 12), two triterpenoids (13 and 14), five lignoids (15-19), curcumin (20), and reference controls niclosamide (21) and valinomycin (22) were potent inhibitors at concentrations between 3.3 and 10 microM. The concentrations of the 22 compounds to inhibit 50% of Vero E6 cell proliferation (CC50) and viral replication (EC50) were measured. The selective index values (SI = CC50/EC50) of the most potent compounds 1, 5, 6, 8, 14, and 16 were 58, >510, 111, 193, 180, and >667, respectively. Betulinic acid (13) and savinin (16) were competitive inhibitors of SARS-CoV 3CL protease with Ki values = 8.2 +/- 0.7 and 9.1 +/- 2.4 microM, respectively. Our findings suggest that specific abietane-type diterpenoids and lignoids exhibit strong anti-SARS-CoV effects.
|
Inhibition of SARS virus-induced cytopathogenicity in Vero E6 cells at 3.3 uM
|
SARS coronavirus
|
25.0
%
|
|
Journal : J. Med. Chem.
Title : Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus.
Year : 2007
Volume : 50
Issue : 17
First Page : 4087
Last Page : 4095
Authors : Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS.
Abstract : In this study, 221 phytocompounds were evaluated for activity against anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) activities using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Ten diterpenoids (1-10), two sesquiterpenoids (11 and 12), two triterpenoids (13 and 14), five lignoids (15-19), curcumin (20), and reference controls niclosamide (21) and valinomycin (22) were potent inhibitors at concentrations between 3.3 and 10 microM. The concentrations of the 22 compounds to inhibit 50% of Vero E6 cell proliferation (CC50) and viral replication (EC50) were measured. The selective index values (SI = CC50/EC50) of the most potent compounds 1, 5, 6, 8, 14, and 16 were 58, >510, 111, 193, 180, and >667, respectively. Betulinic acid (13) and savinin (16) were competitive inhibitors of SARS-CoV 3CL protease with Ki values = 8.2 +/- 0.7 and 9.1 +/- 2.4 microM, respectively. Our findings suggest that specific abietane-type diterpenoids and lignoids exhibit strong anti-SARS-CoV effects.
|
Inhibition of SARS virus-induced cytopathogenicity in Vero E6 cells at 1 uM
|
SARS coronavirus
|
50.0
%
|
|
Journal : J. Med. Chem.
Title : Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus.
Year : 2007
Volume : 50
Issue : 17
First Page : 4087
Last Page : 4095
Authors : Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS.
Abstract : In this study, 221 phytocompounds were evaluated for activity against anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) activities using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Ten diterpenoids (1-10), two sesquiterpenoids (11 and 12), two triterpenoids (13 and 14), five lignoids (15-19), curcumin (20), and reference controls niclosamide (21) and valinomycin (22) were potent inhibitors at concentrations between 3.3 and 10 microM. The concentrations of the 22 compounds to inhibit 50% of Vero E6 cell proliferation (CC50) and viral replication (EC50) were measured. The selective index values (SI = CC50/EC50) of the most potent compounds 1, 5, 6, 8, 14, and 16 were 58, >510, 111, 193, 180, and >667, respectively. Betulinic acid (13) and savinin (16) were competitive inhibitors of SARS-CoV 3CL protease with Ki values = 8.2 +/- 0.7 and 9.1 +/- 2.4 microM, respectively. Our findings suggest that specific abietane-type diterpenoids and lignoids exhibit strong anti-SARS-CoV effects.
|
Antiviral activity against SARS coronavirus in Vero E6 cells assessed as inhibition of viral replication by ELISA
|
SARS coronavirus
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus.
Year : 2007
Volume : 50
Issue : 17
First Page : 4087
Last Page : 4095
Authors : Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY, Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur LF, Yang NS.
Abstract : In this study, 221 phytocompounds were evaluated for activity against anti-severe acute respiratory syndrome associated coronavirus (SARS-CoV) activities using a cell-based assay measuring SARS-CoV-induced cytopathogenic effect on Vero E6 cells. Ten diterpenoids (1-10), two sesquiterpenoids (11 and 12), two triterpenoids (13 and 14), five lignoids (15-19), curcumin (20), and reference controls niclosamide (21) and valinomycin (22) were potent inhibitors at concentrations between 3.3 and 10 microM. The concentrations of the 22 compounds to inhibit 50% of Vero E6 cell proliferation (CC50) and viral replication (EC50) were measured. The selective index values (SI = CC50/EC50) of the most potent compounds 1, 5, 6, 8, 14, and 16 were 58, >510, 111, 193, 180, and >667, respectively. Betulinic acid (13) and savinin (16) were competitive inhibitors of SARS-CoV 3CL protease with Ki values = 8.2 +/- 0.7 and 9.1 +/- 2.4 microM, respectively. Our findings suggest that specific abietane-type diterpenoids and lignoids exhibit strong anti-SARS-CoV effects.
|
Antiproliferative activity against human PC3 cells after 120 hrs by MTT assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Identifying off-target effects and hidden phenotypes of drugs in human cells.
Year : 2006
Volume : 2
Issue : 6
First Page : 329
Last Page : 337
Authors : MacDonald ML, Lamerdin J, Owens S, Keon BH, Bilter GK, Shang Z, Huang Z, Yu H, Dias J, Minami T, Michnick SW, Westwick JK.
Abstract : We present a strategy for identifying off-target effects and hidden phenotypes of drugs by directly probing biochemical pathways that underlie therapeutic or toxic mechanisms in intact, living cells. High-content protein-fragment complementation assays (PCAs) were constructed with synthetic fragments of a mutant fluorescent protein ('Venus', EYFP or both), allowing us to measure spatial and temporal changes in protein complexes in response to drugs that activate or inhibit particular pathways. One hundred and seven different drugs from six therapeutic areas were screened against 49 different PCA reporters for ten cellular processes. This strategy reproduced known structure-function relationships and also predicted 'hidden,' potent antiproliferative activities for four drugs with novel mechanisms of action, including disruption of mitochondrial membrane potential. A simple algorithm identified a 25-assay panel that was highly predictive of antiproliferative activity, and the predictive power of this approach was confirmed with cross-validation tests. This study suggests a strategy for therapeutic discovery that identifies novel, unpredicted mechanisms of drug action and thereby enhances the productivity of drug-discovery research.
|
Antiproliferative activity against human A549 cells after 120 hrs by MTT assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Identifying off-target effects and hidden phenotypes of drugs in human cells.
Year : 2006
Volume : 2
Issue : 6
First Page : 329
Last Page : 337
Authors : MacDonald ML, Lamerdin J, Owens S, Keon BH, Bilter GK, Shang Z, Huang Z, Yu H, Dias J, Minami T, Michnick SW, Westwick JK.
Abstract : We present a strategy for identifying off-target effects and hidden phenotypes of drugs by directly probing biochemical pathways that underlie therapeutic or toxic mechanisms in intact, living cells. High-content protein-fragment complementation assays (PCAs) were constructed with synthetic fragments of a mutant fluorescent protein ('Venus', EYFP or both), allowing us to measure spatial and temporal changes in protein complexes in response to drugs that activate or inhibit particular pathways. One hundred and seven different drugs from six therapeutic areas were screened against 49 different PCA reporters for ten cellular processes. This strategy reproduced known structure-function relationships and also predicted 'hidden,' potent antiproliferative activities for four drugs with novel mechanisms of action, including disruption of mitochondrial membrane potential. A simple algorithm identified a 25-assay panel that was highly predictive of antiproliferative activity, and the predictive power of this approach was confirmed with cross-validation tests. This study suggests a strategy for therapeutic discovery that identifies novel, unpredicted mechanisms of drug action and thereby enhances the productivity of drug-discovery research.
|
Antiproliferative activity against human LoVo cells after 120 hrs by MTT assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Identifying off-target effects and hidden phenotypes of drugs in human cells.
Year : 2006
Volume : 2
Issue : 6
First Page : 329
Last Page : 337
Authors : MacDonald ML, Lamerdin J, Owens S, Keon BH, Bilter GK, Shang Z, Huang Z, Yu H, Dias J, Minami T, Michnick SW, Westwick JK.
Abstract : We present a strategy for identifying off-target effects and hidden phenotypes of drugs by directly probing biochemical pathways that underlie therapeutic or toxic mechanisms in intact, living cells. High-content protein-fragment complementation assays (PCAs) were constructed with synthetic fragments of a mutant fluorescent protein ('Venus', EYFP or both), allowing us to measure spatial and temporal changes in protein complexes in response to drugs that activate or inhibit particular pathways. One hundred and seven different drugs from six therapeutic areas were screened against 49 different PCA reporters for ten cellular processes. This strategy reproduced known structure-function relationships and also predicted 'hidden,' potent antiproliferative activities for four drugs with novel mechanisms of action, including disruption of mitochondrial membrane potential. A simple algorithm identified a 25-assay panel that was highly predictive of antiproliferative activity, and the predictive power of this approach was confirmed with cross-validation tests. This study suggests a strategy for therapeutic discovery that identifies novel, unpredicted mechanisms of drug action and thereby enhances the productivity of drug-discovery research.
|
Antiproliferative activity against human U87MG cells after 120 hrs by MTT assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Identifying off-target effects and hidden phenotypes of drugs in human cells.
Year : 2006
Volume : 2
Issue : 6
First Page : 329
Last Page : 337
Authors : MacDonald ML, Lamerdin J, Owens S, Keon BH, Bilter GK, Shang Z, Huang Z, Yu H, Dias J, Minami T, Michnick SW, Westwick JK.
Abstract : We present a strategy for identifying off-target effects and hidden phenotypes of drugs by directly probing biochemical pathways that underlie therapeutic or toxic mechanisms in intact, living cells. High-content protein-fragment complementation assays (PCAs) were constructed with synthetic fragments of a mutant fluorescent protein ('Venus', EYFP or both), allowing us to measure spatial and temporal changes in protein complexes in response to drugs that activate or inhibit particular pathways. One hundred and seven different drugs from six therapeutic areas were screened against 49 different PCA reporters for ten cellular processes. This strategy reproduced known structure-function relationships and also predicted 'hidden,' potent antiproliferative activities for four drugs with novel mechanisms of action, including disruption of mitochondrial membrane potential. A simple algorithm identified a 25-assay panel that was highly predictive of antiproliferative activity, and the predictive power of this approach was confirmed with cross-validation tests. This study suggests a strategy for therapeutic discovery that identifies novel, unpredicted mechanisms of drug action and thereby enhances the productivity of drug-discovery research.
|
Antiplasmodial activity against Plasmodium falciparum 3D7 after 72 hrs by SYBR green assay
|
Plasmodium falciparum
|
0.89
nM
|
|
Antiplasmodial activity against Plasmodium falciparum 3D7 after 72 hrs by SYBR green assay
|
Plasmodium falciparum
|
794.33
nM
|
|
Journal : Nat. Chem. Biol.
Title : Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
Year : 2009
Volume : 5
Issue : 10
First Page : 765
Last Page : 771
Authors : Yuan J, Johnson RL, Huang R, Wichterman J, Jiang H, Hayton K, Fidock DA, Wellems TE, Inglese J, Austin CP, Su XZ.
Abstract : Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.
|
Antiplasmodial activity against Plasmodium falciparum 7G8 after 72 hrs by SYBR green assay
|
Plasmodium falciparum 7G8
|
0.89
nM
|
|
Antiplasmodial activity against Plasmodium falciparum 7G8 after 72 hrs by SYBR green assay
|
Plasmodium falciparum 7G8
|
794.33
nM
|
|
Journal : Nat. Chem. Biol.
Title : Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
Year : 2009
Volume : 5
Issue : 10
First Page : 765
Last Page : 771
Authors : Yuan J, Johnson RL, Huang R, Wichterman J, Jiang H, Hayton K, Fidock DA, Wellems TE, Inglese J, Austin CP, Su XZ.
Abstract : Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.
|
Antiplasmodial activity against Plasmodium falciparum D10 after 72 hrs by SYBR green assay
|
Plasmodium falciparum D10
|
1.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
Year : 2009
Volume : 5
Issue : 10
First Page : 765
Last Page : 771
Authors : Yuan J, Johnson RL, Huang R, Wichterman J, Jiang H, Hayton K, Fidock DA, Wellems TE, Inglese J, Austin CP, Su XZ.
Abstract : Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.
|
Antiplasmodial activity against Plasmodium falciparum Dd2 after 72 hrs by SYBR green assay
|
Plasmodium falciparum
|
1.48
nM
|
|
Journal : Nat. Chem. Biol.
Title : Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
Year : 2009
Volume : 5
Issue : 10
First Page : 765
Last Page : 771
Authors : Yuan J, Johnson RL, Huang R, Wichterman J, Jiang H, Hayton K, Fidock DA, Wellems TE, Inglese J, Austin CP, Su XZ.
Abstract : Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.
|
Antiplasmodial activity against Plasmodium falciparum GB4 after 72 hrs by SYBR green assay
|
Plasmodium falciparum
|
0.74
nM
|
|
Antiplasmodial activity against Plasmodium falciparum GB4 after 72 hrs by SYBR green assay
|
Plasmodium falciparum
|
794.33
nM
|
|
Journal : Nat. Chem. Biol.
Title : Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
Year : 2009
Volume : 5
Issue : 10
First Page : 765
Last Page : 771
Authors : Yuan J, Johnson RL, Huang R, Wichterman J, Jiang H, Hayton K, Fidock DA, Wellems TE, Inglese J, Austin CP, Su XZ.
Abstract : Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.
|
Antiplasmodial activity against Plasmodium falciparum HB3 after 72 hrs by SYBR green assay
|
Plasmodium falciparum HB3
|
0.89
nM
|
|
Antiplasmodial activity against Plasmodium falciparum HB3 after 72 hrs by SYBR green assay
|
Plasmodium falciparum HB3
|
794.33
nM
|
|
Journal : Nat. Chem. Biol.
Title : Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
Year : 2009
Volume : 5
Issue : 10
First Page : 765
Last Page : 771
Authors : Yuan J, Johnson RL, Huang R, Wichterman J, Jiang H, Hayton K, Fidock DA, Wellems TE, Inglese J, Austin CP, Su XZ.
Abstract : Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.
|
Antiplasmodial activity against Plasmodium falciparum W2 after 72 hrs by SYBR green assay
|
Plasmodium falciparum
|
0.56
nM
|
|
Antiplasmodial activity against Plasmodium falciparum W2 after 72 hrs by SYBR green assay
|
Plasmodium falciparum
|
501.19
nM
|
|
Journal : Nat. Chem. Biol.
Title : Genetic mapping of targets mediating differential chemical phenotypes in Plasmodium falciparum.
Year : 2009
Volume : 5
Issue : 10
First Page : 765
Last Page : 771
Authors : Yuan J, Johnson RL, Huang R, Wichterman J, Jiang H, Hayton K, Fidock DA, Wellems TE, Inglese J, Austin CP, Su XZ.
Abstract : Studies of gene function and molecular mechanisms in Plasmodium falciparum are hampered by difficulties in characterizing and measuring phenotypic differences between individual parasites. We screened seven parasite lines for differences in responses to 1,279 bioactive chemicals. Hundreds of compounds were active in inhibiting parasite growth; 607 differential chemical phenotypes, defined as pairwise IC(50) differences of fivefold or more between parasite lines, were cataloged. We mapped major determinants for three differential chemical phenotypes between the parents of a genetic cross, and we identified target genes by fine mapping and testing the responses of parasites in which candidate genes were genetically replaced with mutant alleles. Differential sensitivity to dihydroergotamine methanesulfonate (1), a serotonin receptor antagonist, was mapped to a gene encoding the homolog of human P-glycoprotein (PfPgh-1). This study identifies new leads for antimalarial drugs and demonstrates the utility of a high-throughput chemical genomic strategy for studying malaria traits.
|
Inhibition of STAT3 in human HeLa cells after 24 hrs by luciferase reporter gene assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway.
Year : 2010
Volume : 1
Issue : 9
First Page : 454
Last Page : 459
Authors : Ren X, Duan L, He Q, Zhang Z, Zhou Y, Wu D, Pan J, Pei D, Ding K, Ding K.
Abstract : Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers with constitutively active STAT3. In this study, we report the identification of niclosamide, an FDA-approved anthelmintic drug, as a new small-molecule inhibitor of the STAT3 signaling pathway. This compound potently inhibited the activation and transcriptional function of STAT3 and consequently induced cell growth inhibition, apoptosis, and cell cycle arrest of cancer cells with constitutively active STAT3. Our study provides a new promising lead compound with a salicylic amide scaffold for the development of STAT3 pathway inhibitors as novel molecularly targeted anticancer drugs.
|
Antiproliferative activity against human DU145 cells after 72 hrs by MTT assay
|
Homo sapiens
|
700.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway.
Year : 2010
Volume : 1
Issue : 9
First Page : 454
Last Page : 459
Authors : Ren X, Duan L, He Q, Zhang Z, Zhou Y, Wu D, Pan J, Pei D, Ding K, Ding K.
Abstract : Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers with constitutively active STAT3. In this study, we report the identification of niclosamide, an FDA-approved anthelmintic drug, as a new small-molecule inhibitor of the STAT3 signaling pathway. This compound potently inhibited the activation and transcriptional function of STAT3 and consequently induced cell growth inhibition, apoptosis, and cell cycle arrest of cancer cells with constitutively active STAT3. Our study provides a new promising lead compound with a salicylic amide scaffold for the development of STAT3 pathway inhibitors as novel molecularly targeted anticancer drugs.
|
Growth inhibition of human DU145 cells assessed as inhibition of colony formation after 11 to 12 days by crystal violet staining based microscopic analysis
|
Homo sapiens
|
700.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Identification of Niclosamide as a New Small-Molecule Inhibitor of the STAT3 Signaling Pathway.
Year : 2010
Volume : 1
Issue : 9
First Page : 454
Last Page : 459
Authors : Ren X, Duan L, He Q, Zhang Z, Zhou Y, Wu D, Pan J, Pei D, Ding K, Ding K.
Abstract : Inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling pathway has been considered a novel therapeutic strategy to treat human cancers with constitutively active STAT3. In this study, we report the identification of niclosamide, an FDA-approved anthelmintic drug, as a new small-molecule inhibitor of the STAT3 signaling pathway. This compound potently inhibited the activation and transcriptional function of STAT3 and consequently induced cell growth inhibition, apoptosis, and cell cycle arrest of cancer cells with constitutively active STAT3. Our study provides a new promising lead compound with a salicylic amide scaffold for the development of STAT3 pathway inhibitors as novel molecularly targeted anticancer drugs.
|
Antiviral activity against HCV genotype 1b infected in Ava5 cells assessed as inhibition of viral replication after 3 days by blot hybridization analysis
|
Hepatitis C virus subtype 1b
|
160.0
nM
|
|
Journal : J. Med. Chem.
Title : Thiazolides as novel antiviral agents. 2. Inhibition of hepatitis C virus replication.
Year : 2011
Volume : 54
Issue : 24
First Page : 8670
Last Page : 8680
Authors : Stachulski AV, Pidathala C, Row EC, Sharma R, Berry NG, Lawrenson AS, Moores SL, Iqbal M, Bentley J, Allman SA, Edwards G, Helm A, Hellier J, Korba BE, Semple JE, Rossignol JF.
Abstract : We report the activities of a number of thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) of thiazolides against HCV are less predictable than against hepatitis B virus (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among the related salicyloylanilides, the m-fluorophenyl analogue was most promising; niclosamide and close analogues suffered from very low solubility and bioavailability. Nitazoxanide (NTZ) 1 has performed well in clinical trials against HCV. We show here that the 5'-Cl analogue 4 has closely comparable in vitro activity and a good cell safety index. By use of support vector analysis, a quantitative structure-activity relationship (QSAR) model was obtained, showing good predictive models for cell safety. We conclude by updating the mode of action of the thiazolides and explain the candidate selection that has led to compound 4 entering preclinical development.
|
Cytotoxicity against human ER negative MDA-MB-231 cells after 72 hrs by MTS assay
|
Homo sapiens
|
790.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of O-Alkylamino Tethered Niclosamide Derivatives as Potent and Orally Bioavailable Anticancer Agents.
Year : 2013
Volume : 4
Issue : 2
First Page : 180
Last Page : 185
Authors : Chen H, Yang Z, Ding C, Chu L, Zhang Y, Terry K, Liu H, Shen Q, Zhou J.
Abstract : Niclosamide has been identified to potently inhibit the activation, nuclear translocation, and transactivation of STAT3. Nevertheless, the poor aqueous solubility and bioavailability of niclosamide has hindered its further clinical development for cancer therapy. To discover new molecules with enhanced drug-like properties, a series of novel O-alkylamino tethered derivatives of niclosamide have been designed, synthesized, and biologically evaluated. Among them, compound 11 (HJC0152) has been demonstrated to significantly suppress MDA-MB-231 xenograft tumor growth in vivo (i.p. & p.o.), indicating its great potential as efficacious and orally bioavailable therapeutics for human cancer.
|
CYtotoxicity against ER-negative human MDA-MB-231 cells by MTS assay
|
Homo sapiens
|
790.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Fragment-based drug design and identification of HJC0123, a novel orally bioavailable STAT3 inhibitor for cancer therapy.
Year : 2013
Volume : 62
First Page : 498
Last Page : 507
Authors : Chen H, Yang Z, Ding C, Chu L, Zhang Y, Terry K, Liu H, Shen Q, Zhou J.
Abstract : Fragment-based drug design (FBDD) is a promising approach for the generation of lead molecules with enhanced activity and especially drug-like properties against therapeutic targets. Herein, we report the fragment-based drug design, systematic chemical synthesis and pharmacological evaluation of novel scaffolds as potent anticancer agents by utilizing six privileged fragments from known STAT3 inhibitors. Several new molecules such as compounds 5, 12, and 19 that may act as advanced chemical leads have been identified. The most potent compound 5 (HJC0123) has demonstrated to inhibit STAT3 promoter activity, downregulate phosphorylation of STAT3, increase the expression of cleaved caspase-3, inhibit cell cycle progression and promote apoptosis in breast and pancreatic cancer cells with low micromolar to nanomolar IC50 values. Furthermore, compound 5 significantly suppressed estrogen receptor (ER)-negative breast cancer MDA-MB-231 xenograft tumor growth in vivo (p.o.), indicating its great potential as an efficacious and orally bioavailable drug candidate for human cancer therapy.
|
Inhibition of Wnt3A/beta-casein signaling in HEK293 cells after 8 hrs by TOPflash reporter assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Small molecule modulators of Wnt/β-catenin signaling.
Year : 2013
Volume : 23
Issue : 7
First Page : 2187
Last Page : 2191
Authors : Mook RA, Chen M, Lu J, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signal transduction pathway is dysregulated in many highly prevalent diseases, including cancer. Unfortunately, drug discovery efforts have been hampered by the paucity of targets and drug-like lead molecules amenable to drug discovery. Recently, we reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling by a unique mechanism, though the target responsible remains unknown. We interrogated the mechanism and structure-activity relationships to understand drivers of potency and to assist target identification efforts. We found inhibition of Wnt signaling by Niclosamide appears unique among the structurally-related anthelmintic agents tested and found the potency and functional response was dependent on small changes in the chemical structure of Niclosamide. Overall, these findings support efforts to identify the target of Niclosamide inhibition of Wnt/β-catenin signaling and the discovery of potent and selective modulators to treat human disease.
|
DNDI: Leish (axenic) in Vitro, 72 hour
|
Leishmania donovani
|
150.0
nM
|
|
Title : Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning
Authors : Kaiser M, Mäser P, Tadoori LP, Ioset JR, Brun R.
Abstract : In this study, a set of 100 registered drugs with drug repositioning potential for neglected tropical diseases was assembled. The compound collection was systematically screened against protozoan parasites, namely T. b. rhodesiense, L. donovani, T. cruzi and P. falciparum. Several drugs and drug classes exhibited in vitro activity and selectivity against one of the protozoan parasites. The results offer opportunities for drug repurposing and the identified compound classes could also be a starting point for new drug discovery projects. See also publication: Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning. PLoS One. 2015 10(8): e0135556.
|
DNDI: Leish (macro) in Vitro, 96 hour
|
Leishmania donovani
|
310.0
nM
|
|
Title : Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning
Authors : Kaiser M, Mäser P, Tadoori LP, Ioset JR, Brun R.
Abstract : In this study, a set of 100 registered drugs with drug repositioning potential for neglected tropical diseases was assembled. The compound collection was systematically screened against protozoan parasites, namely T. b. rhodesiense, L. donovani, T. cruzi and P. falciparum. Several drugs and drug classes exhibited in vitro activity and selectivity against one of the protozoan parasites. The results offer opportunities for drug repurposing and the identified compound classes could also be a starting point for new drug discovery projects. See also publication: Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning. PLoS One. 2015 10(8): e0135556.
|
PubChem BioAssay. SW480 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
1.0
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. RKO viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
1.0
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. Decreased HeLa cell count-IC50. (Class of assay: confirmatory)
|
None
|
144.0
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. HCT116 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
1.44
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. SNU-C1 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
472.85
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. VEGF stimulated ADSC/ECFC co-culture CD31-stained tube area decrease-IC50. (Class of assay: confirmatory)
|
None
|
112.0
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. Colo320 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
8.26
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. DLD-1 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
3.49
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. GSK3B-pretreated HCT116 viability from Cell TiterGlo-IC50. (Class of assay: confirmatory)
|
None
|
2.95
nM
|
|
Title : PubChem BioAssay data set
|
Inhibition of Wnt/beta-catenin in HEK293 cells assessed as inhibition of Wnt3A-stimulated TOPFlash activity after 8 hrs
|
Homo sapiens
|
340.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Cytotoxicity against human HCT116 cells assessed as growth inhibition after 72 hrs by MTS assay
|
Homo sapiens
|
450.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Cytotoxicity against human breast cancer cells assessed as growth inhibition after 72 hrs by Cell Titer Glo Assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Cytotoxicity against human colon cancer cells assessed as growth inhibition after 72 hrs by Cell Titer Glo Assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Cytotoxicity against human lung cancer cells assessed as growth inhibition after 72 hrs by Cell Titer Glo Assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Cytotoxicity against human prostate cancer cells assessed as growth inhibition after 72 hrs by Cell Titer Glo Assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Cytotoxicity against human ovarian cancer cells assessed as growth inhibition after 72 hrs by Cell Titer Glo Assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Cytotoxicity against human blood cancer cells assessed as growth inhibition after 72 hrs by Cell Titer Glo Assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Cytotoxicity against human pancreatic cancer cells assessed as growth inhibition after 72 hrs by Cell Titer Glo Assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.
Year : 2015
Volume : 23
Issue : 17
First Page : 5829
Last Page : 5838
Authors : Mook RA, Wang J, Ren XR, Chen M, Spasojevic I, Barak LS, Lyerly HK, Chen W.
Abstract : The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.
|
Inhibition of Wnt/beta-catenin signaling (unknown origin) expressed in HEK293 cells assessed as inhibition of Wnt3A-stimulated beta-catenin response transcription after 6 hrs by TOPflash dual luciferase reporter gene assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis.
Year : 2017
Volume : 25
Issue : 6
First Page : 1804
Last Page : 1816
Authors : Mook RA, Ren XR, Wang J, Piao H, Barak LS, Kim Lyerly H, Chen W.
Abstract : The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.
|
Effect on ATP homeostasis in human HCT116 cells assessed as reduction in ATP level after 3 hrs in absence of glucose by ATP bioluminescent assay
|
Homo sapiens
|
56.0
nM
|
|
Effect on ATP homeostasis in human HCT116 cells assessed as reduction in ATP level after 3 hrs in absence of glucose by ATP bioluminescent assay
|
Homo sapiens
|
250.0
nM
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis.
Year : 2017
Volume : 25
Issue : 6
First Page : 1804
Last Page : 1816
Authors : Mook RA, Ren XR, Wang J, Piao H, Barak LS, Kim Lyerly H, Chen W.
Abstract : The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.
|
Inhibition of Wnt/beta-catenin signaling (unknown origin) expressed in HEK293 cells assessed as inhibition of Wnt3A-stimulated beta-catenin response transcription at 0.16 uM after 6 hrs by TOPflash dual luciferase reporter gene assay relative to control
|
Homo sapiens
|
40.0
%
|
|
Journal : Bioorg Med Chem
Title : Benzimidazole inhibitors from the Niclosamide chemotype inhibit Wnt/β-catenin signaling with selectivity over effects on ATP homeostasis.
Year : 2017
Volume : 25
Issue : 6
First Page : 1804
Last Page : 1816
Authors : Mook RA, Ren XR, Wang J, Piao H, Barak LS, Kim Lyerly H, Chen W.
Abstract : The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.
|
Antiviral activity against Chikungunya virus infected in BHK-21 cells by RT-qPCR analysis
|
Chikungunya virus
|
950.0
nM
|
|
Journal : Bioorg Med Chem
Title : The medicinal chemistry of Chikungunya virus.
Year : 2017
Volume : 25
Issue : 16
First Page : 4219
Last Page : 4244
Authors : da Silva-Júnior EF, Leoncini GO, Rodrigues ÉES, Aquino TM, Araújo-Júnior JX.
Abstract : Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds.
|
Antiviral activity against Chikungunya virus 0611aTw infected in BHK-21 cells by RT-qPCR analysis
|
Chikungunya virus
|
850.0
nM
|
|
Journal : Bioorg Med Chem
Title : The medicinal chemistry of Chikungunya virus.
Year : 2017
Volume : 25
Issue : 16
First Page : 4219
Last Page : 4244
Authors : da Silva-Júnior EF, Leoncini GO, Rodrigues ÉES, Aquino TM, Araújo-Júnior JX.
Abstract : Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds.
|
Antiviral activity against Chikungunya virus 0810bTw infected in BHK-21 cells by RT-qPCR analysis
|
Chikungunya virus
|
900.0
nM
|
|
Journal : Bioorg Med Chem
Title : The medicinal chemistry of Chikungunya virus.
Year : 2017
Volume : 25
Issue : 16
First Page : 4219
Last Page : 4244
Authors : da Silva-Júnior EF, Leoncini GO, Rodrigues ÉES, Aquino TM, Araújo-Júnior JX.
Abstract : Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds.
|
Antiviral activity against Chikungunya virus infected in human U2OS cells by RT-qPCR analysis
|
Chikungunya virus
|
360.0
nM
|
|
Journal : Bioorg Med Chem
Title : The medicinal chemistry of Chikungunya virus.
Year : 2017
Volume : 25
Issue : 16
First Page : 4219
Last Page : 4244
Authors : da Silva-Júnior EF, Leoncini GO, Rodrigues ÉES, Aquino TM, Araújo-Júnior JX.
Abstract : Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds.
|
Inhibition of Wnt3A-stimulated Wnt/beta-catenin pathway in HEK293 cells transfected with p8xTOPFlash, Renilla luciferase plasmid pRL-TK and pLKO.1 after 6 hrs by Dual topflash luciferase reporter assay
|
Homo sapiens
|
450.0
nM
|
|
Journal : Bioorg Med Chem
Title : Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth.
Year : 2018
Volume : 26
Issue : 20
First Page : 5435
Last Page : 5442
Authors : Wang J, Mook RA, Ren XR, Zhang Q, Jing G, Lu M, Spasojevic I, Lyerly HK, Hsu D, Chen W.
Abstract : The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.
|
Antiproliferative activity against human SW948 cells after 72 hrs by colorimetric MTS assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : Bioorg Med Chem
Title : Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth.
Year : 2018
Volume : 26
Issue : 20
First Page : 5435
Last Page : 5442
Authors : Wang J, Mook RA, Ren XR, Zhang Q, Jing G, Lu M, Spasojevic I, Lyerly HK, Hsu D, Chen W.
Abstract : The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.
|
Antiproliferative activity against human HT-29 cells after 72 hrs by colorimetric MTS assay
|
Homo sapiens
|
130.0
nM
|
|
Journal : Bioorg Med Chem
Title : Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth.
Year : 2018
Volume : 26
Issue : 20
First Page : 5435
Last Page : 5442
Authors : Wang J, Mook RA, Ren XR, Zhang Q, Jing G, Lu M, Spasojevic I, Lyerly HK, Hsu D, Chen W.
Abstract : The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.
|
Antiproliferative activity against human HCT116 cells after 72 hrs by colorimetric MTS assay
|
Homo sapiens
|
410.0
nM
|
|
Journal : Bioorg Med Chem
Title : Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth.
Year : 2018
Volume : 26
Issue : 20
First Page : 5435
Last Page : 5442
Authors : Wang J, Mook RA, Ren XR, Zhang Q, Jing G, Lu M, Spasojevic I, Lyerly HK, Hsu D, Chen W.
Abstract : The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.
|
Antiproliferative activity against human CRC240 cells after 72 hrs by colorimetric MTS assay
|
Homo sapiens
|
890.0
nM
|
|
Journal : Bioorg Med Chem
Title : Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth.
Year : 2018
Volume : 26
Issue : 20
First Page : 5435
Last Page : 5442
Authors : Wang J, Mook RA, Ren XR, Zhang Q, Jing G, Lu M, Spasojevic I, Lyerly HK, Hsu D, Chen W.
Abstract : The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.
|
Antiproliferative activity against human SW480 cells after 72 hrs by colorimetric MTS assay
|
Homo sapiens
|
980.0
nM
|
|
Journal : Bioorg Med Chem
Title : Identification of DK419, a potent inhibitor of Wnt/β-catenin signaling and colorectal cancer growth.
Year : 2018
Volume : 26
Issue : 20
First Page : 5435
Last Page : 5442
Authors : Wang J, Mook RA, Ren XR, Zhang Q, Jing G, Lu M, Spasojevic I, Lyerly HK, Hsu D, Chen W.
Abstract : The Wnt signaling pathway is critical for normal tissue development and is an underlying mechanism of disease when dysregulated. Previously, we reported that the drug Niclosamide inhibits Wnt/β-catenin signaling by decreasing the cytosolic levels of Dishevelled and β-catenin, and inhibits the growth of colon cancers both in vitro and in vivo. Since the discovery of Niclosamide's anthelmintic activity, a growing body of literature indicates that Niclosamide is a multifunctional drug. In an effort to identify derivatives of Niclosamide with improved pharmacokinetic properties that maintain the multifunctional drug activity of Niclosamide for clinical evaluation, we designed DK419, a derivative containing a 1H-benzo[d]imidazole-4-carboxamide substructure, using the structure-activity relationships (SAR) of the Niclosamide salicylanilide chemotype. Similar to Niclosamide, we found DK419 inhibited Wnt/β-catenin signaling, altered cellular oxygen consumption rate and induced production of pAMPK. Moreover, we found DK419 inhibited the growth of CRC tumor cells in vitro, had good plasma exposure when dosed orally, and inhibited the growth of patient derived CRC240 tumor explants in mice dosed orally. DK419, a derivative of Niclosamide with multifunctional activity and improved pharmacokinetic properties, is a promising agent to treat colorectal cancer, Wnt-related diseases and other diseases in which Niclosamide has demonstrated functional activity.
|
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
|
-35.91
%
|
|
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.
|
Antiviral activity against SARS-CoV-2 (viral titer) measured by plaque assay in Vero cells at MOI 0.0125 after 24 hr
|
Chlorocebus sabaeus
|
280.0
nM
|
|
Title : Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs
Year : 2020
Authors : Sangeun Jeon, Meehyun Ko, Jihye Lee, Inhee Choi, Soo Young Byun, Soonju Park, David Shum, Seungtaek Kim
Abstract : COVID-19 is an emerging infectious disease and was recently declared as a pandemic by WHO. Currently, there is no vaccine or therapeutic available for this disease. Drug repositioning represents the only feasible option to address this global challenge and a panel of 48 FDA- approved drugs that have been pre-selected by an assay of SARS-CoV was screened to identify potential antiviral drug candidates against SARS-CoV-2 infection. We found a total of 24 drugs which exhibited antiviral efficacy (0.1 μM < IC50 < 10 μM) against SARS-CoV-2. In particular, two FDA-approved drugs - niclosamide and ciclesonide – were notable in some respects. These drugs will be tested in an appropriate animal model for their antiviral activities. In near future, these already FDA-approved drugs could be further developed following clinical trials in order to provide additional therapeutic options for patients with COVID-19.
|
Inhibition of Wnt3A-stimulated Wnt/beta-catenin pathway in HEK293 cells transfected with p8xTOPFlash, Renilla luciferase plasmid pRL-TK and pLKO.1 after 8 hrs by Dual topflash luciferase reporter gene assay
|
Homo sapiens
|
340.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human HCT116 cells cytosol lysate harboring beta-catenin mutation assessed as reduction in Axin2 protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
35.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human HCT116 cells cytosol lysate harboring beta-catenin mutation assessed as reduction in beta-catenin protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
46.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human HCT116 whole cell lysate harboring beta-catenin mutation assessed as reduction in c-Myc protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
1.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human HCT116 whole cell lysate harboring beta-catenin mutation assessed as reduction in survivin protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
44.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human HCT116 whole cell lysate harboring beta-catenin mutation assessed as reduction in cyclin D1 protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
28.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human SW480 cells cytosol lysate harboring APC mutation assessed as reduction in Axin2 protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
29.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human SW480 cells cytosol lysate harboring APC mutation assessed as reduction in beta-catenin protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
74.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human SW480 whole cell lysate harboring APC mutation assessed as reduction in c-Myc protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
3.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human SW480 whole cell lysate harboring APC mutation assessed as reduction in survivin protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
41.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Inhibition of Wnt/beta-catenin signaling pathway in human SW480 whole cell lysate harboring APC mutation assessed as reduction in cyclin D1 protein expression at 5 uM after 18 hrs by Western blot analysis relative to control
|
Homo sapiens
|
45.0
%
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel triazole inhibitors of Wnt/β-catenin signaling based on the Niclosamide chemotype.
Year : 2019
Volume : 29
Issue : 2
First Page : 317
Last Page : 321
Authors : Mook RA, Wang J, Ren XR, Piao H, Lyerly HK, Chen W.
Abstract : Dysregulation of the Wnt signaling pathway is an underlying mechanism in multiple diseases, particularly in cancer. Until recently, identifying agents that target this pathway has been difficult and as a result, no approved drugs exist that specifically target this pathway. We reported previously that the anthelmintic drug Niclosamide inhibits the Wnt/β-catenin signaling pathway and suppresses colorectal cancer cell growth in vitro and in vivo. In an effort to build on this finding, we sought to discover new Wnt/β-catenin inhibitors that expanded the chemotype structural diversity. Here, we asked a specific SAR question unresolved in previous SAR studies of Niclosamide's inhibition of Wnt/β-catenin signaling to identify a new structural class of Wnt/β-catenin signaling inhibitors based on a triazole motif. Similar to Niclosamide, we found that the new triazole derivatives internalized Frizzled-1 GFP receptors, inhibited Wnt/β-catenin signaling in the TOPflash assay and reduced Wnt/β-catenin target gene levels in CRC cells harboring mutations in the Wnt pathway. Moreover, in pilot SAR studies, we found the Wnt/β-catenin SAR trends in the anilide region were generally similar between the two chemical classes of inhibitors. Overall, these studies demonstrate the ability to use the SAR of the Niclosamide salicylanilide chemical class to expand the structural diversity of Wnt/β-catenin inhibitors.
|
Cytotoxicity against human HL60 cells incubated for 3 days by CellTiter-Glo luminescent assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway.
Year : 2019
Volume : 29
Issue : 16
First Page : 2307
Last Page : 2315
Authors : Chae HD, Cox N, Capolicchio S, Lee JW, Horikoshi N, Kam S, Ng AA, Edwards J, Butler TL, Chan J, Lee Y, Potter G, Capece MC, Liu CW, Wakatsuki S, Smith M, Sakamoto KM.
Abstract : Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.
|
Cytotoxicity against human KG1 cells incubated for 3 days by CellTiter-Glo luminescent assay
|
Homo sapiens
|
360.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway.
Year : 2019
Volume : 29
Issue : 16
First Page : 2307
Last Page : 2315
Authors : Chae HD, Cox N, Capolicchio S, Lee JW, Horikoshi N, Kam S, Ng AA, Edwards J, Butler TL, Chan J, Lee Y, Potter G, Capece MC, Liu CW, Wakatsuki S, Smith M, Sakamoto KM.
Abstract : Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.
|
Cytotoxicity against human Jurkat cells incubated for 3 days by CellTiter-Glo luminescent assay
|
Homo sapiens
|
400.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway.
Year : 2019
Volume : 29
Issue : 16
First Page : 2307
Last Page : 2315
Authors : Chae HD, Cox N, Capolicchio S, Lee JW, Horikoshi N, Kam S, Ng AA, Edwards J, Butler TL, Chan J, Lee Y, Potter G, Capece MC, Liu CW, Wakatsuki S, Smith M, Sakamoto KM.
Abstract : Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.
|
Cytotoxicity against human NALM6 cells incubated for 3 days by CellTiter-Glo luminescent assay
|
Homo sapiens
|
620.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : SAR optimization studies on modified salicylamides as a potential treatment for acute myeloid leukemia through inhibition of the CREB pathway.
Year : 2019
Volume : 29
Issue : 16
First Page : 2307
Last Page : 2315
Authors : Chae HD, Cox N, Capolicchio S, Lee JW, Horikoshi N, Kam S, Ng AA, Edwards J, Butler TL, Chan J, Lee Y, Potter G, Capece MC, Liu CW, Wakatsuki S, Smith M, Sakamoto KM.
Abstract : Disruption of cyclic adenosine monophosphate response element binding protein (CREB) provides a potential new strategy to address acute leukemia, a disease associated with poor prognosis, and for which conventional treatment options often carry a significant risk of morbidity and mortality. We describe the structure-activity relationships (SAR) for a series of XX-650-23 derived from naphthol AS-E phosphate that disrupts binding and activation of CREB by the CREB-binding protein (CBP). Through the development of this series, we identified several salicylamides that are potent inhibitors of acute leukemia cell viability through inhibition of CREB-CBP interaction. Among them, a biphenyl salicylamide, compound 71, was identified as a potent inhibitor of CREB-CBP interaction with improved physicochemical properties relative to previously described derivatives of naphthol AS-E phosphate.
|
Antiparasitic activity against Toxoplasma gondii
|
Toxoplasma gondii
|
0.0453
ug.mL-1
|
|
Journal : Eur J Med Chem
Title : Recent progress on anti-Toxoplasma drugs discovery: Design, synthesis and screening.
Year : 2019
Volume : 183
First Page : 111711
Last Page : 111711
Authors : Deng Y, Wu T, Zhai SQ, Li CH.
Abstract : Toxoplasma gondii severely threaten the health of immunocompromised patients and pregnant women as this parasite can cause several disease, including brain and eye disease. Current treatment for toxoplasmosis commonly have high cytotoxic side effects on host and require long durations ranging from one week to more than one year. The regiments lack efficacy to eradicate T. gondii tissue cysts to cure chromic infection results in the needs for long treatment and relapsing disease. In addition, there has not been approved drugs for treating the pregnant women infected by T. gondii. Moreover, Toxoplasma vaccine researches face a wide variety of challenges. Developing high efficient and low toxic agents against T. gondii is urgent and important. Over the last decade, tremendous progress have been made in identifying and developing novel compounds for the treatment of toxoplasmosis. This review summarized and discussed recent advances between 2009 and 2019 in exploring effective agents against T. gondii from five aspects of drug discovery.
|
Antiviral activity against Human adenovirus 5 infected in 293beta5 cells assessed as inhibition of plaque formation at 10 uM incubated for 7 days by GFP reporter gene assay relative to control
|
Human adenovirus 5
|
100.0
%
|
|
Journal : J Med Chem
Title : Structure-Activity Relationship Studies on Diversified Salicylamide Derivatives as Potent Inhibitors of Human Adenovirus Infection.
Year : 2020
Volume : 63
Issue : 6
First Page : 3142
Last Page : 3160
Authors : Xu J, Berastegui-Cabrera J, Chen H, Pachón J, Zhou J, Sánchez-Céspedes J.
Abstract : The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (11, 13, 14, 17, 20, 58, 60, 62, and 70) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC50 values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds 13, 62, and 70 exert their activities in the HAdV entry pathway, while compounds 14 and 60 likely target the HAdV DNA replication, and 11, 17, 20, and 58 inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections.
|
Antiviral activity against Human adenovirus 5 infected in 293beta5 cells assessed as inhibition of plaque formation incubated for 7 days by GFP reporter gene assay
|
Human adenovirus 5
|
600.0
nM
|
|
Journal : J Med Chem
Title : Structure-Activity Relationship Studies on Diversified Salicylamide Derivatives as Potent Inhibitors of Human Adenovirus Infection.
Year : 2020
Volume : 63
Issue : 6
First Page : 3142
Last Page : 3160
Authors : Xu J, Berastegui-Cabrera J, Chen H, Pachón J, Zhou J, Sánchez-Céspedes J.
Abstract : The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (11, 13, 14, 17, 20, 58, 60, 62, and 70) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC50 values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds 13, 62, and 70 exert their activities in the HAdV entry pathway, while compounds 14 and 60 likely target the HAdV DNA replication, and 11, 17, 20, and 58 inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections.
|
Antiviral activity against Human adenovirus 5 infected in human A549 cells assessed as inhibition of viral entry at 50 uM after 48 hrs by GFP reporter gene based assay relative to control
|
Human adenovirus 5
|
100.0
%
|
|
Journal : J Med Chem
Title : Structure-Activity Relationship Studies on Diversified Salicylamide Derivatives as Potent Inhibitors of Human Adenovirus Infection.
Year : 2020
Volume : 63
Issue : 6
First Page : 3142
Last Page : 3160
Authors : Xu J, Berastegui-Cabrera J, Chen H, Pachón J, Zhou J, Sánchez-Céspedes J.
Abstract : The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (11, 13, 14, 17, 20, 58, 60, 62, and 70) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC50 values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds 13, 62, and 70 exert their activities in the HAdV entry pathway, while compounds 14 and 60 likely target the HAdV DNA replication, and 11, 17, 20, and 58 inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections.
|
Antiproliferative activity against human LN229 cells after 5 days by AlamarBlue assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of small molecules targeting glioblastoma.
Year : 2019
Volume : 164
First Page : 8
Last Page : 26
Authors : Fernandes GFDS, Fernandes BC, Valente V, Dos Santos JL.
Abstract : Glioblastoma (GBM) is one of the most common central nervous system cancers. It is characterized as a fast-growing tumor that arises from multiple cell types with neural stem-cell-like properties. Additionally, GBM tumors are highly invasive, which is attributed to the presence of glioblastoma stem cells that makes surgery ineffective in most cases. Currently, temozolomide is the unique chemotherapy option approved by the U.S. Food and Drug Administration for GBM treatment. This review analyzes the emergence and development of new synthetic small molecules discovered as promising anti-glioblastoma agents. A number of compounds were described herein and grouped according to the main chemical class used in the drug discovery process. Importantly, we focused only on synthetic compounds published in the last 10 years, thus excluding natural products. Furthermore, we included in this review only those most biologically active compounds with proven in vitro and/or in vivo efficacy.
|
Antiproliferative activity against human T98G cells after 5 days by AlamarBlue assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of small molecules targeting glioblastoma.
Year : 2019
Volume : 164
First Page : 8
Last Page : 26
Authors : Fernandes GFDS, Fernandes BC, Valente V, Dos Santos JL.
Abstract : Glioblastoma (GBM) is one of the most common central nervous system cancers. It is characterized as a fast-growing tumor that arises from multiple cell types with neural stem-cell-like properties. Additionally, GBM tumors are highly invasive, which is attributed to the presence of glioblastoma stem cells that makes surgery ineffective in most cases. Currently, temozolomide is the unique chemotherapy option approved by the U.S. Food and Drug Administration for GBM treatment. This review analyzes the emergence and development of new synthetic small molecules discovered as promising anti-glioblastoma agents. A number of compounds were described herein and grouped according to the main chemical class used in the drug discovery process. Importantly, we focused only on synthetic compounds published in the last 10 years, thus excluding natural products. Furthermore, we included in this review only those most biologically active compounds with proven in vitro and/or in vivo efficacy.
|
Antiproliferative activity against human U87 cells after 5 days by AlamarBlue assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of small molecules targeting glioblastoma.
Year : 2019
Volume : 164
First Page : 8
Last Page : 26
Authors : Fernandes GFDS, Fernandes BC, Valente V, Dos Santos JL.
Abstract : Glioblastoma (GBM) is one of the most common central nervous system cancers. It is characterized as a fast-growing tumor that arises from multiple cell types with neural stem-cell-like properties. Additionally, GBM tumors are highly invasive, which is attributed to the presence of glioblastoma stem cells that makes surgery ineffective in most cases. Currently, temozolomide is the unique chemotherapy option approved by the U.S. Food and Drug Administration for GBM treatment. This review analyzes the emergence and development of new synthetic small molecules discovered as promising anti-glioblastoma agents. A number of compounds were described herein and grouped according to the main chemical class used in the drug discovery process. Importantly, we focused only on synthetic compounds published in the last 10 years, thus excluding natural products. Furthermore, we included in this review only those most biologically active compounds with proven in vitro and/or in vivo efficacy.
|
Antiproliferative activity against human U138MG cells after 5 days by AlamarBlue assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of small molecules targeting glioblastoma.
Year : 2019
Volume : 164
First Page : 8
Last Page : 26
Authors : Fernandes GFDS, Fernandes BC, Valente V, Dos Santos JL.
Abstract : Glioblastoma (GBM) is one of the most common central nervous system cancers. It is characterized as a fast-growing tumor that arises from multiple cell types with neural stem-cell-like properties. Additionally, GBM tumors are highly invasive, which is attributed to the presence of glioblastoma stem cells that makes surgery ineffective in most cases. Currently, temozolomide is the unique chemotherapy option approved by the U.S. Food and Drug Administration for GBM treatment. This review analyzes the emergence and development of new synthetic small molecules discovered as promising anti-glioblastoma agents. A number of compounds were described herein and grouped according to the main chemical class used in the drug discovery process. Importantly, we focused only on synthetic compounds published in the last 10 years, thus excluding natural products. Furthermore, we included in this review only those most biologically active compounds with proven in vitro and/or in vivo efficacy.
|
Antiproliferative activity against human U373 cells after 5 days by AlamarBlue assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent advances in the discovery of small molecules targeting glioblastoma.
Year : 2019
Volume : 164
First Page : 8
Last Page : 26
Authors : Fernandes GFDS, Fernandes BC, Valente V, Dos Santos JL.
Abstract : Glioblastoma (GBM) is one of the most common central nervous system cancers. It is characterized as a fast-growing tumor that arises from multiple cell types with neural stem-cell-like properties. Additionally, GBM tumors are highly invasive, which is attributed to the presence of glioblastoma stem cells that makes surgery ineffective in most cases. Currently, temozolomide is the unique chemotherapy option approved by the U.S. Food and Drug Administration for GBM treatment. This review analyzes the emergence and development of new synthetic small molecules discovered as promising anti-glioblastoma agents. A number of compounds were described herein and grouped according to the main chemical class used in the drug discovery process. Importantly, we focused only on synthetic compounds published in the last 10 years, thus excluding natural products. Furthermore, we included in this review only those most biologically active compounds with proven in vitro and/or in vivo efficacy.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
28.67
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
5.92
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
10.92
%
|
|
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
|
32.08
%
|
|
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
|
14.78
%
|
|
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
|
14.57
%
|
|
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
|
32.08
%
|
|
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
|
14.78
%
|
|
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
|
14.57
%
|
|
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.
|
Antiviral activity against GFP-fused Human adenovirus 5 infected in 293beta5 cells assessed as inhibition of plaque formation incubated for 7 days by GFP reporter gene assay
|
Human adenovirus 5
|
600.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors.
Year : 2020
Volume : 63
Issue : 21
First Page : 12830
Last Page : 12852
Authors : Xu J,Berastegui-Cabrera J,Ye N,Carretero-Ledesma M,Pachón-Díaz J,Chen H,Pachón-Ibáñez ME,Sánchez-Céspedes J,Zhou J
Abstract : An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC = 0.27 μM), significantly decreased cytotoxicity (CC = 156.8 μM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections.
|
Antiviral activity against Human adenovirus 5 infected in 293beta5 cells assessed as inhibition of plaque formation at 10 uM incubated for 7 days by GFP reporter gene assay relative to control
|
Human adenovirus 5
|
100.0
%
|
|
Journal : J Med Chem
Title : Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors.
Year : 2020
Volume : 63
Issue : 21
First Page : 12830
Last Page : 12852
Authors : Xu J,Berastegui-Cabrera J,Ye N,Carretero-Ledesma M,Pachón-Díaz J,Chen H,Pachón-Ibáñez ME,Sánchez-Céspedes J,Zhou J
Abstract : An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC = 0.27 μM), significantly decreased cytotoxicity (CC = 156.8 μM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections.
|
Antiviral activity against wild-type Human adenovirus 5 infected in human A549 cells assessed as inhibition of virus entry at 50 uM incubated for 48 hrs by fluorescence assay relative to control
|
Human adenovirus 5
|
100.0
%
|
|
Journal : J Med Chem
Title : Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors.
Year : 2020
Volume : 63
Issue : 21
First Page : 12830
Last Page : 12852
Authors : Xu J,Berastegui-Cabrera J,Ye N,Carretero-Ledesma M,Pachón-Díaz J,Chen H,Pachón-Ibáñez ME,Sánchez-Céspedes J,Zhou J
Abstract : An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC = 0.27 μM), significantly decreased cytotoxicity (CC = 156.8 μM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections.
|
Antiviral activity against Human adenovirus 5 infected in 293beta5 cells assessed as inhibition of virus infection at 10 fold IC50 measured after 60 mins by GFP reporter gene assay relative to control
|
Human adenovirus 5
|
50.0
%
|
|
Journal : J Med Chem
Title : Discovery of Novel Substituted N-(4-Amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide Analogues as Potent Human Adenovirus Inhibitors.
Year : 2020
Volume : 63
Issue : 21
First Page : 12830
Last Page : 12852
Authors : Xu J,Berastegui-Cabrera J,Ye N,Carretero-Ledesma M,Pachón-Díaz J,Chen H,Pachón-Ibáñez ME,Sánchez-Céspedes J,Zhou J
Abstract : An effective therapy for human adenovirus (HAdV) infections in immunocompromised patients and healthy individuals with community-acquired pneumonia remains an unmet medical need. We herein reported a series of novel substituted N-(4-amino-2-chlorophenyl)-5-chloro-2-hydroxybenzamide analogues as potent HAdV inhibitors. Compounds 6, 15, 29, 40, 43, 46, 47, and 54 exhibited increased selectivity indexes (SI > 100) compared to the lead compound niclosamide, while maintaining sub-micromolar to low micromolar potency against HAdV. The preliminary mechanistic studies indicated that compounds 6 and 43 possibly target the HAdV DNA replication process, while compounds 46 and 47 suppress later steps of HAdV life cycle. Notably, among these derivatives, compound 15 showed improved anti-HAdV activity (IC = 0.27 μM), significantly decreased cytotoxicity (CC = 156.8 μM), and low in vivo toxicity (maximum tolerated dose = 150 mg/kg in hamster) as compared with niclosamide, supporting its further in vivo efficacy studies for the treatment of HAdV infections.
|
Antiproliferative activity against human MDA-MB-231 cells assessed as inhibition of cell viability at 10 uM after 48 hrs by MTT assay relative to control
|
Homo sapiens
|
91.54
%
|
|
|
Antiproliferative activity against human HCT116 cells assessed as inhibition of cell viability at 10 uM after 48 hrs by MTT assay relative to control
|
Homo sapiens
|
73.77
%
|
|
|
Antiproliferative activity against human SW480 cells assessed as inhibition of cell viability at 10 uM after 48 hrs by MTT assay relative to control
|
Homo sapiens
|
76.81
%
|
|
|
Antiproliferative activity against human L3.6 cells assessed as inhibition of cell viability at 10 uM after 48 hrs by MTT assay relative to control
|
Homo sapiens
|
66.16
%
|
|
|
Antiproliferative activity against human MDA-MB-231 cells assessed as inhibition of cell viability after 48 hrs by MTT assay
|
Homo sapiens
|
800.0
nM
|
|
|
Antiproliferative activity against human HCT-116 cells assessed as inhibition of cell viability after 48 hrs by MTT assay
|
Homo sapiens
|
450.0
nM
|
|
|
Inhibition of STAT3 phosphorylation in human MDA-MB-231 cells by sandwich ELISA
|
Homo sapiens
|
210.0
nM
|
|
|
Inhibition of STAT3 promoter activity in human MDA-MB-231 cells at 1 uM incubated for 24 hrs by dual luciferase reporter assay
|
Homo sapiens
|
88.2
%
|
|
|
Inhibition of NS-1in Zika virus
|
Zika virus
|
570.0
nM
|
|
|
Inhibition of envelope protein in Zika virus
|
Zika virus
|
880.0
nM
|
|
|
Antiviral activity against Zika virus infected in SNB-19 cells assessed as reduction in viral titer
|
Homo sapiens
|
120.0
nM
|
|
|
Antiviral activity against SARS Cov-2 infected in Vero cells assessed as inhibition of viral cytopathic effect measured after 72 hrs by CellTiter-Glo luminescent cell viability assay
|
Severe acute respiratory syndrome coronavirus 2
|
280.0
nM
|
|
|
Antiviral activity against SARS Cov-2 USA_WA1/2020 infected in Vero E6 cells assessed as inhibition of viral cytopathic effect measured after 72 hrs by CellTiter-Glo luminescent cell viability assay
|
Severe acute respiratory syndrome coronavirus 2
|
112.0
nM
|
|
