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Purity: ≥98%
Danusertib (formerly PHA-739358), a pyrrolo-pyrazole compound, is a potent Aurora kinase inhibitor of Aurora A/B/C with potential antitumor activity. It inhibits Aurora A/B/C with IC50s of 13 nM, 79 nM and 61 nM in cell-free assays, odestly potent to Abl, TrkA, c-RET and FGFR1, and less potent to Lck, VEGFR2/3, c-Kit, CDK2, etc. Danusertib is a potent small-molecule inhibitor of aurora kinases family members with a dominant inhibition for aurora B kinase (ABK). It shows potent in vitro antiproliferative activity and high in vivo antitumor efficacy. It has the potential for treating chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), thyroid prostate and breast carcinoma.
| ln Vitro |
The viability of C13 and A2780cp cells is severely reduced by denusertib (0.01 to 50 μM). After 24 and 48 hours of treatment, the IC50s for C13 cells are 10.40 and 1.83 μM, and for A2780cp cells, they are 19.89 and 3.88 μM. In C13 and A2780cp cells, dunusertib promotes a cell arrest cycle in the G2/M phase. After being treated with denusertib, the proportion of cells arrested in the G2/M phase rises noticeably, and polyploidy accumulates in C13 and A2780cp cells. Danusertib increases the expression of p21 Waf1/Cip1, p27 Kip1, and p53 while depressing CDK1/CDC2 and cyclin B1 expression. Danusertib activates the PI3K/Akt/mTOR signaling pathway in C13 and A2780cp cells to cause autophagy[1]. All examined leukemic cell lines are significantly inhibited from proliferating by PHA-739358, with IC50 values ranging from 0.05 μM to 3.06 μM. IM-resistant M351T, E255K, and T315I mutants are among the BaF3-p210 cells in which PHA-739358 exerts antiproliferative effects. BaF3 -p210 wt cells and IM-resistant mutants exhibit decreased phosphorylation of CrkL in response to PHA-739358 (5 μM)[2]. In vitro, dacartib totally prevents GEP-NET cell proliferation and induces cell-cycle arrest[3].
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| ln Vivo |
PHA-739358 (15 mg/kg twice day, ip) and IM are well tolerated; over the course of the 10-day treatment period, they virtually suppressed tumor growth and significantly inhibited K562 cell proliferation[2]. When compared to controls or mice given streptozotocine/5-fluorouracil, danusertibsertib (2×15 mg/kg/d, ip) dramatically slows down the growth of tumors in vivo in a subcutaneous murine xenograft model[3].
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| References |
[1]. Zi D, et al. Danusertib Induces Apoptosis, Cell Cycle Arrest, and Autophagy but Inhibits Epithelial to Mesenchymal Transition Involving PI3K/Akt/mTOR Signaling Pathway in Human Ovarian Cancer Cells. Int J Mol Sci. 2015 Nov 13;16(11):27228-51.
[2]. Gontarewicz A, et al. Simultaneous targeting of Aurora kinases and Bcr-Abl kinase by the small molecule inhibitor PHA-739358 is effective against imatinib-resistant BCR-ABL mutations including T315I. Blood. 2008 Apr 15;111(8):4355-64. [3]. Fraedrich K, et al. Targeting Aurora Kinases with Danusertib (PHA-739358) Inhibits Growth of Liver Metastases from Gastroenteropancreatic Neuroendocrine Tumors in an Orthotopic Xenograft Model. Clin Cancer Res. 2012 Sep 1;18(17):4621-32. Epub 2012 Jul 2 |
| Molecular Formula |
C26H30N6O3
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| Molecular Weight |
474.55
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| CAS # |
827318-97-8
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| Related CAS # |
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| SMILES |
O=C(N1CC2=C(NN=C2NC(C3=CC=C(N4CCN(CC4)C)C=C3)=O)C1)[C@@H](C5=CC=CC=C5)OC
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.38 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 1% DMSO +30% polyethylene glycol+1% Tween 80 : 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1073 mL | 10.5363 mL | 21.0726 mL | |
| 5 mM | 0.4215 mL | 2.1073 mL | 4.2145 mL | |
| 10 mM | 0.2107 mL | 1.0536 mL | 2.1073 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00872300 | Terminated | Drug: PHA-739358 | Multiple Myeloma | Nerviano Medical Sciences | October 2008 | Phase 2 |
| NCT00766324 | Completed | Drug: PHA-739358 | Metastatic Hormone Refractory Prostate Cancer |
Nerviano Medical Sciences | September 2007 | Phase 2 |
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Inhibition of cellular pathways by PHA-739358. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3158-68. |
PHA-739358 treatment results in the inhibition of tumor growth in TRAMP mice as assessed by MRI evaluation. Mol Cancer Ther. 2007 Dec;6(12 Pt 1):3158-68. |
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