Danusertib (PHA-739358) [827318-97-8]
Referência A4116-10mg
Tamanho : 10mg
Marca : APExBIO Technology
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Danusertib (PHA-739358)
Danusertib (previously known as PHA-739358), a 3-aminopyrazole derivative identified during the development of the pyrrolopyrazole sub-series, is a potent small-molecule inhibitor of aurora kinases family members with a dominant inhibition for aurora B kinase (ABK). This pan-aurora kinases inhibitor is also able to inhibit several tyrosine kinases, including T315I mutant, Ret, Trk-A and fibroblast growth factor receptor-1 (FGFR-1), which are involved in multiple malignancies, such as chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), thyroid prostate and breast carcinoma. Thus, in many previous studies, danusertib exhibits remarkable antitumor activity in a number of different xengorafts, spontaneous, and transgenic animal tumor models with a favorable pharmacokinetic and safety profile.
Reference
Carpinelli P, Ceruti R, Giorgini ML, Cappella P, Gianellini L, Croci V, Degrassi A, Texido G, Rocchetti M, Vianello P, Rusconi L, Storici P, Zugnoni P, Arrigoni C, Soncini C, Alli C, Patton V, Marsiglio A, Ballinari D, Pesenti E, Fancelli D, Moll J. PHA-739358, a potent inhibitor of aurora kinases with a selecyive target inhibiton profile relevant to cancer. Mol Cancer Ther 2007; 6(12 Pt 1): 3158-3168
- 1. Wang R, Yang JF, et al. "Bromodomain-Containing Protein BRD4 Is Hyperphosphorylated in Mitosis." Cancers (Basel). 2020;12(6):E1637. PMID:32575711
- 2. Wang H, Tian L, et al. "The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability." Cancer Cell. 2018 Nov 12;34(5):823-839.e7. PMID:30423299
- 3. Wang H, Tian L, et al. "Bone-in-culture array as a platform to model early-stage bone metastases and discover anti-metastasis therapies." Nat Commun. 2017 Apr 21;8:15045. PMID:28429794
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 474.55 |
| Cas No. | 827318-97-8 |
| Formula | C26H30N6O3 |
| Synonyms | 5-Amido-pyrrolopyrazole 9d |
| Solubility | ≥23.75 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O |
| Chemical Name | N-[5-[(2R)-2-methoxy-2-phenylacetyl]-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide |
| SDF | Download SDF |
| Canonical SMILES | CN1CCN(CC1)C2=CC=C(C=C2)C(=O)NC3=NNC4=C3CN(C4)C(=O)C(C5=CC=CC=C5)OC |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Kinase experiment [1]: | |
| Biochemical kinase assays | The Km values for ATP and the specific substrate were initially determined, and each assay was 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 experiment [2]: | |
| Cell lines | CD34+ cells |
| Preparation method | The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20 °C for several months. |
| Reaction Conditions | 5 μM; 5 days |
| Applications | In CD34+ cells from an IM-resistant CML patient, Danusertib induced apoptosis and reduced phosphorylation of P-CrkL. |
| Animal experiment [2]: | |
| Animal models | Female SCID mice s.c. injected with K562 cells |
| Dosage form | 15 mg/kg; i.p.; b.i.d., for 10 days |
| Applications | Danusertib significantly inhibited K562 cell proliferation and virtually suppressed tumor growth. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: [1]. Carpinelli P, Ceruti R, Giorgini ML, Cappella P, Gianellini L, Croci V, Degrassi A, Texido G, Rocchetti M, Vianello P, Rusconi L, Storici P, Zugnoni P, Arrigoni C, Soncini C, Alli C, Patton V, Marsiglio A, Ballinari D, Pesenti E, Fancelli D, Moll J. PHA-739358, a potent inhibitor of aurora kinases with a selecyive target inhibiton profile relevant to cancer. Mol Cancer Ther 2007; 6(12 Pt 1): 3158-3168. [2]. Gontarewicz A, Balabanov S, Keller G, Colombo R, Graziano A, Pesenti E, Benten D, Bokemeyer C, Fiedler W, Moll J, Brümmendorf TH. 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. | |
| Description | Danusertib (PHA-739358) is an inhibitor of Aurora kinase for Aurora A/B/C with IC50 of 13 nM/79 nM/61 nM, modestly potent to Abl, TrkA, c-RET and FGFR1, and less potent to Lck, VEGFR2/3, c-Kit, CDK2, etc | |||||
| Targets | Aurora A/B/C | Bcr-Abl | c-RET | FGFR | TrkA | |
| IC50 | 13 nM/79 nM/61 nM | 25nM | 31 nM | 47 nM | 30 nM | |
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