10074-G5 is a potent inhibitor of c-Myc-Max dimerization and interaction with an IC50 of 146 μM and with anticancer activities. 10074-G5 binds to and distorts the bHLH-ZIP domain of c-Myc, thereby inhibiting c-Myc/Max heterodimer formation and inhibiting its transcriptional activity. In vitro, 10074-G5 inhibited the growth of Daudi Burkitt's lymphoma cells and disrupted c-Myc/Max dimerization. 10074-G5 had no effect on the growth of Daudi xenografts in C.B-17 SCID mice that were treated with 20 mg/kg 10074-G5 intravenously for 5 consecutive days. Inhibition of c-Myc/Max dimerization in Daudi xenografts was not seen 2 or 24 h after treatment.
理化性质和储存条件
| Molecular Weight (MW) | 332.31 |
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| Formula | C18H12N4O3 |
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| CAS No. | 413611-93-5 |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 60 mg/mL (180.5 mM) |
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| Water: <1 mg/mL |
| Ethanol: 10 mg/mL (30.0 mM) |
| SMILES | O=[N+](C1=CC=C(NC2=CC=CC=C2C3=CC=CC=C3)C4=CNON41)[O-] |
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| Synonyms | 10074-G5; 10074G5; 10074 G5 |
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实验参考方法
| In Vitro | In vitro activity: 10074-G5 inhibits the growth of Daudi Burkitt's lymphoma cells and disruptes c-Myc/Max dimerization. The IC50 values against Daudi and HL-60 cells are 15.6 and 13.5 μM, respectively. 10074-G5 binds the Myc peptide Myc353-437 with a Kd value of 2.8 μM in the region Arg363-Ile381. 10074-G5 binds in a cavity that is created by a kink (Asp379-Ile381) in the N-terminus of an induced helical domain (Leu370–Arg378.
Kinase Assay: 10074-G5 is a potent inhibitor of c-Myc-Max dimerization and interaction with an IC50 of 146 μM and with anticancer activities. 10074-G5 binds to and distorts the bHLH-ZIP domain of c-Myc, thereby inhibiting c-Myc/Max heterodimer formation and inhibiting its transcriptional activity.
Cell Assay: 10074-G5 is dissolved in DMSO and diluted with culture medium. Daudi cells or HL-60 cells in logarithmic growth are treated with 10074-G5 (1-100 μM). After 72 h, 50 μL of 1 mg/mL MTT is added to each well and incubated for 4 h. At the end of the incubation, medium containing drug and MTT is removed from each well, and 100 μl of DMSO is added, followed by shaking for 5 min. The absorbance at 570 nm is read. |
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| In Vivo | The plasma half-life of 10074-G5 in mice treated with 20 mg/kg i.v. is 37 min, and peak plasma concentration is 58 μM, which is 10-fold higher than peak tumor concentration. The lack of antitumor activity probably is caused by the rapid metabolism of 10074-G5 to inactive metabolites, resulting in tumor concentrations of 10074-G5 insufficient to inhibit c-Myc/Max dimerization. Plasma 10074-G5 peak concentration (Cmax) of 58.5 ± 2.7 nmol/ml is observed at 5 min after intravenous administration of 20 mg/kg to mice bearing Daudi xenografts, 10074-G5 concentration in plasma declines rapidly. Except for lung, liver, and fat, tissue concentrations of 10074-G5 are lower than those of plasma at all time points. |
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| Animal model | Specific-pathogen-free, female C.B-17 SCID mice. |
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| Formulation & Dosage | Dissolved in Cremophor EL/ethanol/saline (1:1:8, v/v/v); 20 mg/kg; i.v. injection. |
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| References | Bioorg Med Chem Lett. 2013 Jan 1;23(1):370-4; J Pharmacol Exp Ther. 2010 Dec;335(3):715-27. |
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