Target Validation Information
Target ID T96144
Target Name DNA topoisomerase II
Target Type
Successful
Drug Potency against Target Quinolones Drug Info IC50 = 0.2~4 g/ml [536068]
Idarubicin Drug Info IC50 = 38 nM [552817]
TOPOSTATIN Drug Info IC50 = 4000 nM [526096]
Novobiocin Drug Info IC50 = 10 nM [553237]
PIROXANTRONE Drug Info IC50 = 4600 nM [529301]
Gemifloxacin Drug Info MIC50 = 0.002 ug/ml [552333]
Doxorubicin Drug Info IC50 = 66.3 nM [552817]
DEMETHYLZEYLASTERONE Drug Info IC50 = 17600 nM [526181]
LOSOXANTRONE Drug Info IC50 = 7300 nM [529301]
Garenoxacin Drug Info MIC50 = 0.03 ug/ml [552333]
A-62176 Drug Info IC50 = 510 nM [534726]
Olean-12-en-3beta,15alpha-diol Drug Info IC50 = 17500 nM [526233]
LUPEOL Drug Info IC50 = 10400 nM [526233]
Action against Disease Model Fleroxacin The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk. [552184] Drug Info
Amsacrine HERG-Lite monitors the expression of hERG at the cell surface in two different stable mammalian cell lines. One cell line acts as a biosensor for drugs that inhibit hERG trafficking, while the other predicts hERG blockers based on their ability to act as pharmacological chaperones. In this study, we have validated the HERG-Lite assay using a panel of 100 drugs: 50 hERG blockers and 50 nonblockers.HERG-Lite correctly predicted hERG risk for all 100 test compounds with no false positives or negatives. All 50 hERG blockers were detected as drugs with hERG risk in the HERG-Lite assay, and fell into two classes: B (for blocker) and C (for complex; block and trafficking inhibition). [552526] Drug Info
Enoxacin The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk. [552184] Drug Info
Pefloxacin The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk. [552184] Drug Info
Sparfloxacin The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk. [552184] Drug Info
Norfloxacin The in vivo convulsant activities in rats of five representative fluoroquinolones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxacin, were compared. The experimental approach allowed distinction between the drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic contribution to the convulsant activity by severalfold, and the ratios of concentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of unbound FQs in plasma varied from about 5 to 75% as a function of lipophilicity. Interestingly, FQs with the highest intrinsic convulsant activities had the lowest levels of diffusion in CSF and vice versa. This in vivo approach provides information complementary to that of in vitro experiments and should be recommended for early preclinical assessment of a new FQ's epileptogenic risk. [552184] Drug Info
References
Ref 552184Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats. Antimicrob Agents Chemother. 1999 Jun;43(6):1511-5.
Ref 536068The magic bullets and tuberculosis drug targets. Annu Rev Pharmacol Toxicol. 2005;45:529-64.
Ref 552526HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk. J Pharmacol Toxicol Methods. 2005 Jul-Aug;52(1):136-45.
Ref 552817Mechanism of action of key enzymes associated with cancer propagation and their inhibition by various chemotherapeutic agents. Mini Rev Med Chem. 2008 Apr;8(4):388-98.
Ref 526096J Nat Prod. 2001 Feb;64(2):204-7.Isoaurostatin, a novel topoisomerase inhibitor produced by Thermomonospora alba.
Ref 553237Mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase. Antimicrob Agents Chemother. 1996 Feb;40(2):473-6.
Ref 529301Bioorg Med Chem. 2008 Apr 1;16(7):3959-68. Epub 2008 Jan 26.The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds.
Ref 552333Novel antibacterial agents for the treatment of serious Gram-positive infections. Expert Opin Investig Drugs. 2003 Mar;12(3):379-99.
Ref 552184Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats. Antimicrob Agents Chemother. 1999 Jun;43(6):1511-5.
Ref 552184Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats. Antimicrob Agents Chemother. 1999 Jun;43(6):1511-5.
Ref 552184Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats. Antimicrob Agents Chemother. 1999 Jun;43(6):1511-5.
Ref 552817Mechanism of action of key enzymes associated with cancer propagation and their inhibition by various chemotherapeutic agents. Mini Rev Med Chem. 2008 Apr;8(4):388-98.
Ref 526181J Nat Prod. 2001 Oct;64(10):1294-6.Catalytic inhibition of topoisomerase IIalpha by demethylzeylasterone, a 6-oxophenolic triterpenoid from Kokoona zeylanica.
Ref 529301Bioorg Med Chem. 2008 Apr 1;16(7):3959-68. Epub 2008 Jan 26.The structure-based design, synthesis and biological evaluation of DNA-binding bisintercalating bisanthrapyrazole anticancer compounds.
Ref 552333Novel antibacterial agents for the treatment of serious Gram-positive infections. Expert Opin Investig Drugs. 2003 Mar;12(3):379-99.
Ref 534726J Med Chem. 1998 Oct 22;41(22):4273-8.Design of new topoisomerase II inhibitors based upon a quinobenzoxazine self-assembly model.
Ref 526233J Nat Prod. 2001 Dec;64(12):1545-7.Screening of triterpenoids isolated from Phyllanthus flexuosus for DNA topoisomerase inhibitory activity.
Ref 526233J Nat Prod. 2001 Dec;64(12):1545-7.Screening of triterpenoids isolated from Phyllanthus flexuosus for DNA topoisomerase inhibitory activity.
Ref 552184Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats. Antimicrob Agents Chemother. 1999 Jun;43(6):1511-5.

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