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Danusertib (PHA-739358) Chemical Structure
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Biological Activity
| Information | Danusertib (PHA-739358) is a pyrrolo-pyrazole and small molecule aurora kinases and Bcr-Abl kinase inhibitor for aurora A, B, and C with IC50 of 13 nM, 79 nM, and 61 nM, respectively. | |||||
|---|---|---|---|---|---|---|
| Targets | Aurora A | Aurora B | Aurora C | |||
| IC50 | 13 nM [1] | 79 nM [1] | 61 nM [1] | |||
| In vitro | Danusertib inhibits the activities of other kinases such as FGFR1, Abl, Ret and Trka, with IC50 of 47, 25, 31, and 31 nM, respectively. In a cell assay, after treatment of wild-type and p53-deficient MEFs with danusertib, the wild-type cells undergo an arrest in mitosis (4N) that is maintained for up to 48 h. The p53-deficient cells on the other hand do not arrest at the 4N DNA stage, but continues with additional rounds of DNA synthesis to become >8N. Treatment with danusertib results in an increase in p53 protein levels and an associated increase in p21 protein, which is known to be transcriptionally regulated by p53. [1] Increasing concentrations of Danusertib produces a dose-dependent reduction of cell growth after 48 hours in BCR-ABL–positive (K562, BV173) and BCR-ABL–negative (HL60) cells. [2] | |||||
| In vivo | Administration of 25 mg/kg danusertib bd i.v. to HL-60 xenograft rats results in 75% inhibition of tumor growth with complete regression in one animal. Danusertib results in biomarker modulation accompanied by inhibition of tumor growth. This is compatible with an expected mechanism of action of aurora kinase inhibition. [1] PHA-739358 significantly inhibits proliferation of K562 cells andvirtually suppressed tumor growth during the 10-day treatment period. [2] | |||||
| Clinical Trials | Danusertib is currently in a Phase II clinical trial in the treatment of leukemia. | |||||
| Features | ||||||
Protocol
Kinase Assay: [1]
| Biochemical kinase Assays | The Km values for ATP and the specific substrate are initially determined, and each assay is then run at optimized ATP (2Km) and substrate (5Km) concentrations. This setting enabled direct comparison of IC50 values of Danusertib across the applied kinase selectivity screening panel for the evaluation of the selectivity profile. |
|---|
Cell Assay: [2]
| Cell lines: | CD34+ cells |
|---|---|
| Concentrations: | 5 μM |
| Incubation Time: | 5 days |
| Method: | For short-term expansion assays, 1 × 103 CD34+ cells are plated in triplicates in 96-well plates containing 100 μL of serum-free medium per well supplemented with human stem-cell factor (100 ng/mL), human Flt-3 Ligand (100 ng/mL), human thrombopoietin (50 ng/mL), human interleukin-3 and -6 (IL-3 and IL-6, respectively, both 20 ng/mL), and granulocyte colony-stimulating factor (20 ng/mL) along with Danusertib at the indicated concentrations. After 5 days, an additional 100 μL of cytokine and Danusertib containing medium are added. Cell numbers within each individual well are estimated on days 3, 6, and 9 or on days 3, 6, and 12 for healthy donor samples. |
Animal Study:[2]
| Animal Models: | Female SCID mice |
|---|---|
| Formulation: | In DMSO |
| Dosages: | 15 mg/kg |
| Administration: | Intraperitoneally |
Chemical Information
| Molecular Weight (WM): | 474.55 |
|---|---|
| Formula: | C26H30N6O3 |
| CAS No.: | 827318-97-8 |
| Synonyms: |
N/A
|
| Dissolve in (25°C): | DMSO ≥95mg/mL |
| Water <1mg/mL | |
| Ethanol ≥34mg/mL | |
| Storage: | 2 years-20°CPowder |
| 1 week-4°Cin DMSO | |
| 1 month-80°in DMSO |
Quality Control & MSDS
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For MTT assays, cells (2,000 ~ 5,000 cells/well) were subcultured into 96-well plates according to their growth properties. Cell proliferation was assayed at 72 hr after treatment of PHA-739358 by adding 20 μl of 5 mg/ml 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution per 100 μl of growth medium. After incubating for 3-4 h at 37°C, the media were removed and 150 µl/well of MTT solvent (either absolute DMSO or isopropanol containing 4 mM HCl and 0.1% Nonidet-40) was added to dissolve the formazan. The absorbance of each well was measured by ELx808 (BioTek, Winooski, VT) or Wallac Victor2 (Perkin-Elmer Life Sciences, Boston, MA) Microplate Reader. Viable cells are presented as percent of control, vehicle-treated cells.
For MTT assays, cells (2,000 ~ 5,000 cells/well) were subcultured into 96-well plates according to their growth properties. Cell proliferation was assayed at 72 hr after treatment of PHA-739358 by adding 20 μl of 5 mg/ml 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution per 100 μl of growth medium. After incubating for 3-4 h at 37°C, the media were removed and 150 µl/well of MTT solvent (either absolute DMSO or isopropanol containing 4 mM HCl and 0.1% Nonidet-40) was added to dissolve the formazan. The absorbance of each well was measured by ELx808 (BioTek, Winooski, VT) or Wallac Victor2 (Perkin-Elmer Life Sciences, Boston, MA) Microplate Reader. Viable cells are presented as percent of control, vehicle-treated cells.
Data independently produced by Dr. Yong-Weon Yi from Georgetown University Medical Center. Danusertib (PHA-739358) purchased from Selleck
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Western blot analysis of Histone and Aurora kinase. 0-10μM PHA739358 was added.
Western blot analysis of Histone and Aurora kinase. 0-10μM PHA739358 was added.
Data independently produced by Dr. Zhang of Tianjin Medical University Danusertib (PHA-739358) purchased from Selleck
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For MTT assays, cells (2,000 ~ 5,000 cells/well) were subcultured into 96-well plates according to their growth properties. Cell proliferation was assayed at 72 hr after treatment of PHA-739358 by adding 20 μl of 5 mg/ml 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) solution per 100 μl of growth medium. After incubating for 3-4 h at 37°C, the media were removed and 150 µl/well of MTT solvent (either absolute DMSO or isopropanol containing 4 mM HCl and 0.1% Nonidet-40) was added to dissolve the formazan. The absorbance of each well was measured by ELx808 (BioTek, Winooski, VT) or Wallac Victor2 (Perkin-Elmer Life Sciences, Boston, MA) Microplate Reader. Viable cells are presented as percent of control, vehicle-treated cells. |
Data independently produced by Dr. Yong-Weon Yi from Georgetown University Medical Center.
Western blot analysis of Histone and Aurora kinase. 0-10μM PHA739358 was added. |
Data independently produced by Dr. Zhang of Tianjin Medical University
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