XL228IGF1R/AURORA /FGFR1-3/ABL/SRC family kinases inhibitor CAS# 898280-07-4 |
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Quality Control & MSDS
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| Cas No. | 898280-07-4 | SDF | Download SDF |
| PubChem ID | 59757974 | Appearance | Powder |
| Formula | C22H31N9O | M.Wt | 437.54 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 83.33 mg/mL (190.45 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-(4-methylpiperazin-1-yl)-2-N-[(3-propan-2-yl-1,2-oxazol-5-yl)methyl]pyrimidine-2,4-diamine | ||
| SMILES | CC(C)C1=NOC(=C1)CNC2=NC(=CC(=N2)NC3=NNC(=C3)C4CC4)N5CCN(CC5)C | ||
| Standard InChIKey | ALKJNCZNEOTEMP-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C22H31N9O/c1-14(2)17-10-16(32-29-17)13-23-22-25-19(24-20-11-18(27-28-20)15-4-5-15)12-21(26-22)31-8-6-30(3)7-9-31/h10-12,14-15H,4-9,13H2,1-3H3,(H3,23,24,25,26,27,28) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | XL228 is a multi-targeted tyrosine kinase inhibitor with IC50s of 5, 3.1, 1.6, 6.1, 2 nM for Bcr-Abl, Aurora A, IGF-1R, Src and Lyn, respectively.In Vitro:XL228 shows a broad pattern of protein kinase inhibition, including the tyrosine kinases IGF1R, SRC, ABL, FGFR1‐3, and ALK and the serine/threonine kinases Aurora A and Aurora B. A panel of kinase inhibitors including XL228 is profiled against a series of cancer cell lines with known alterations in major signaling pathways. Approximately 30% of the lines demonstrate XL228 IC50 values of <100nM in viability assays, including many lines with characterized ALK or FGFR mutations or amplifications. XL228 eliminates the phosphorylation of Aurora A and B at concentrations above 10 nM. Short‐term treatment of HeLa cells leads to disruption of mitotic spindle formation, with the majority of mitotic cells exhibiting a unipolar spindle and disorganized chromosomes[2]. It displays low nanomolar biochemical activity against wild type Abl kinase (Ki=5 nM), as well as the T315I form of Abl resistant to imatinib and dasatinib (Ki=1.4 nM). XL228 inhibits phosphorylation of BCR-ABL and its substrate STAT5 in K562 cells in vitro with IC50s of 33 and 43 nM, respectively[3].In Vivo:Single-dose pharmacodynamics studies demonstrate a potent effect of XL228 on BCR-ABL signaling in K562 xenograft tumors. Phosphorylation of BCR-ABL is decreased by 50% at XL228 plasma concentrations of 3.5 μM; a similar decrease in phospho-STAT5 occurred at 0.8 μM plasma concentration[3]. References: | |||||
XL228 Dilution Calculator
XL228 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.2855 mL | 11.4275 mL | 22.8551 mL | 45.7101 mL | 57.1376 mL |
| 5 mM | 0.4571 mL | 2.2855 mL | 4.571 mL | 9.142 mL | 11.4275 mL |
| 10 mM | 0.2286 mL | 1.1428 mL | 2.2855 mL | 4.571 mL | 5.7138 mL |
| 50 mM | 0.0457 mL | 0.2286 mL | 0.4571 mL | 0.9142 mL | 1.1428 mL |
| 100 mM | 0.0229 mL | 0.1143 mL | 0.2286 mL | 0.4571 mL | 0.5714 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Description: IC50 Value: 3 nM (Aurora A Kinase); 5 nM (Ki, Abl)[1] XL228 is a protein kinase inhibitor targeting IGF1R, the AURORA kinases, FGFR1-3, ABL and SRC family kinases. in vitro: Approximately 30% of the lines demonstrated XL228 IC50 values of <100nM in viability assays, including many lines with characterized ALK or FGFR mutations or amplifications. Cell lines showing the highest level of response to XL228 were often sensitive to other Aurora, ALK or FGFR inhibitors as well. Sub-20nM activity was demonstrated against FGFR2 in a cellular kinase ELISA assay, and confirmed by immunoblot analysis. Potency against ALK in the cell kinase assay was lower (approximately200 nM) [2]. in vivo: N/A Toxicity:N/A Clinical trial: Study of XL-228 in Subjects With Chronic Myeloid Leukemia or Philadelphia-Chromosome-Positive Acute Lymphocytic Leukemia. Phase 1
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The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors.[Pubmed:21907495]
Cancer Treat Rev. 2012 Jun;38(4):292-302.
The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have become increasingly recognized as having a driving role in the development of malignancy, and consequently IGF-1R has become a potential target for cancer therapy. Several inhibitors of IGF-1R are in clinical development for the treatment of solid tumors, including non-small cell lung cancer (NSCLC). These IGF-1R-targeted agents include monoclonal antibodies such as cixutumumab (IMC-A12), AMG-479, AVE1642, BIIB022, dalotuzumab (MK-0646), and robatumumab (Sch717454), the ligand neutralizing antibody Medi-573, and the small molecule inhibitors BMS-754807, linsitinib (OSI-906), XL228, and AXL1717. Two phase III trials of the anti-IGF-1R monoclonal antibody, figitumumab (CP-751,871), were discontinued in 2010 as it was considered unlikely either trial would meet their primary endpoints. In light of disappointing clinical data with figitumumab and other targeted agents, it is likely that the use of molecular markers will become important in predicting response to treatment. This review outlines the role of IGF-1R signaling in solid tumors with a particular focus on NSCLC, and provides an overview of clinical data.
Systematic review: functional outcomes and complications of intramedullary nailing versus plate fixation for both-bone diaphyseal forearm fractures in children.[Pubmed:24845408]
Injury. 2014 Aug;45(8):1135-43.
BACKGROUND: Both-bone diaphyseal forearm fractures constitute up to 5.4% of all fractures in children in the United Kingdom. Most can be managed with closed reduction and cast immobilisation. Surgical fixation options include flexible intramedullary nailing and plating. However, the optimal method is controversial. The main purpose of this study was to systematically search for and critically appraise articles comparing functional outcomes, radiographic outcomes and complications of nailing and plating for both-bone diaphyseal forearm fractures in children under 18 years. METHODS: A comprehensive search of Medline, Embase and Cochrane databases using specific search terms and limits was conducted. Articles identified were thoroughly screened using strict eligibility criteria and eight retrospective non-randomised comparative studies were identified and reviewed. RESULTS: There were no statistically significant differences in functional outcome or time to fracture union between plating and IM nailing. No consistent difference was found in complication rate, fracture angulation, shortening or rotation. Better cosmesis and shorter duration of surgery was noted in the IM nailing group. Post-operative radial bow was significantly abnormal in the IM nailing groups, but did not affect forearm movement. CONCLUSION: Based on similar functional and radiographic outcomes, nailing seems to be a safe and effective option when compared to plating for paediatric forearm fractures. However, critical appraisal of the studies in this review identified some methodological deficiencies and further prospective, randomised trials are recommended.
Novel dual Src/Abl inhibitors for hematologic and solid malignancies.[Pubmed:20557276]
Expert Opin Investig Drugs. 2010 Aug;19(8):931-45.
IMPORTANCE OF THE FIELD: c-Src and Bcr-Abl are two non-receptor or cytoplasmic tyrosine kinases (TKs) that play important roles in the development of solid and hematological malignancies. Indeed, Src is overexpressed or hyperactivated in a variety of solid tumors, while Bcr-Abl is the causative agent of chronic myeloid leukemia (CML), where Src is also involved. The two enzymes share significant sequence homology and remarkable structural resemblance. AREAS COVERED IN THIS REVIEW: ATP-competitive compounds originally developed as Src inhibitors, showed to be also potent Abl inhibitors. Dasatinib, the first dual Src/Abl inhibitor approved by the US FDA in 2006 for the treatment of imatinib-resistant CML, is currently being tested in several clinical trials for the treatment of different solid tumors. SKI-606 and AZD0530 are two other important dual Src/Abl inhibitors extensively tested in animal models and in clinical trials, but not entered into therapy yet. WHAT THE READER WILL GAIN: In this review we will report the latest results regarding dasatinib, SKI-606 and AZD0530, but also the knowledge on new compounds that have appeared in the literature in the last few years, including AP24163, AP24534, XL228, DC2036. We will focus on the most recent clinical trials or on preclinical studies that are in progress on these small-molecule TK inhibitors that represent a targeted therapy with high potential against cancer. TAKE HOME MESSAGE: Molecularly targeted therapies, including the inhibition of specific TKs hyperactivated or overexpressed in many human cancers, could be less toxic than the classical non-specific cytotoxic chemotherapeutic agents; they could offer important therapeutic effects, especially if used in association with other agents such as monoclonal antibodies.
