KW 2449Multikinase inhibitor CAS# 1000669-72-6 |
- Linsitinib
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Quality Control & MSDS
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| Cas No. | 1000669-72-6 | SDF | Download SDF |
| PubChem ID | 11427553 | Appearance | Powder |
| Formula | C20H20N4O | M.Wt | 332.4 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | Soluble in DMSO > 10 mM | ||
| Chemical Name | [4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone | ||
| SMILES | C1CN(CCN1)C(=O)C2=CC=C(C=C2)C=CC3=NNC4=CC=CC=C43 | ||
| Standard InChIKey | YYLKKYCXAOBSRM-JXMROGBWSA-N | ||
| Standard InChI | InChI=1S/C20H20N4O/c25-20(24-13-11-21-12-14-24)16-8-5-15(6-9-16)7-10-19-17-3-1-2-4-18(17)22-23-19/h1-10,21H,11-14H2,(H,22,23)/b10-7+ | ||
| 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 | KW 2449 is a multikinase inhibitor of FLT3, ABL, Aurora kinase and FGFR. | |||||
| Targets | FLT3 | FLT3 (D835Y) | Abl | Abl (T315I) | Aurora A | FGFR1 |
| IC50 | 6.6 nM | 1 nM | 14 nM | 4 nM | 48 nM | 36 nM |
KW 2449 Dilution Calculator
KW 2449 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 3.0084 mL | 15.0421 mL | 30.0842 mL | 60.1685 mL | 75.2106 mL |
| 5 mM | 0.6017 mL | 3.0084 mL | 6.0168 mL | 12.0337 mL | 15.0421 mL |
| 10 mM | 0.3008 mL | 1.5042 mL | 3.0084 mL | 6.0168 mL | 7.5211 mL |
| 50 mM | 0.0602 mL | 0.3008 mL | 0.6017 mL | 1.2034 mL | 1.5042 mL |
| 100 mM | 0.0301 mL | 0.1504 mL | 0.3008 mL | 0.6017 mL | 0.7521 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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KW 2449 is a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase with IC50 values of 6.6nM, 14nM, 4nM and 48nM, respectively [1].
KW-2449 is a potent kinase inhibitor against FLT3, ABL, T315I-mutant ABL (ABL-T315I) tyrosine kinases as well as Aurora kinase. In vitro assay shows KW-2449 has the potency of growth inhibition with different mechanisms. In leukemia cells with FLT3 mutations, KW-2449 down-regulates phosphorylated-FLT3/STAT5, induces G1 arrest and apoptosis. KW-2449 also inhibits tumor growth in FLT3-mutated xenograft model. While in leukemia cells with wild-type FLT3, KW-2449 reduces phosphorylated histone H3, induces G2/M arrest and apoptosis. However, it is reported that the AML patients treated with LT3 inhibitors, such as KW-2449, have only partial FLT3 inhibition in vivo. And the plasma level of FL (the ligand of FLT3) appears to rise after chemotherapy, which impeding the efficacy of the FLT3 inhibitors [1, 2].
References:
[1] Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, Ishii K, Mori Y, Ozeki K, Minami Y, Abe A, Maeda H, Akiyama T, Kanda Y, Sato Y, Akinaga S, Naoe T. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood. 2009 Aug 20;114(8):1607-17.
[2] Sato T, Yang X, Knapper S, White P, Smith BD, Galkin S, Small D, Burnett A, Levis M. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. Blood. 2011 Mar 24;117(12):3286-93.
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HDAC inhibitors potentiate the activity of the BCR/ABL kinase inhibitor KW-2449 in imatinib-sensitive or -resistant BCR/ABL+ leukemia cells in vitro and in vivo.[Pubmed:21474579]
Clin Cancer Res. 2011 May 15;17(10):3219-32.
PURPOSE: The purpose of this study was to determine whether histone deacetylase (HDAC) inhibitors (HDACI) such as vorinostat or entinostat (SNDX-275) could increase the lethality of the dual Bcr/Abl-Aurora kinase inhibitor KW-2449 in various Bcr/Abl(+) human leukemia cells, including those resistant to imatinib mesylate (IM). EXPERIMENTAL DESIGN: Bcr/Abl(+) chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) cells, including those resistant to IM (T315I, E255K), were exposed to KW-2449 in the presence or absence of vorinostat or SNDX-275, after which apoptosis and effects on signaling pathways were examined. In vivo studies combining HDACIs and KW2449 were carried out by using a systemic IM-resistant ALL xenograft model. RESULTS: Coadministration of HDACIs synergistically increased KW-2449 lethality in vitro in multiple CML and Ph(+) ALL cell types including human IM resistant cells (e.g., BV-173/E255K and Adult/T315I). Combined treatment resulted in inactivation of Bcr/Abl and downstream targets (e.g., STAT5 and CRKL), as well as increased reactive oxygen species (ROS) generation and DNA damage (gammaH2A.X). The latter events and cell death were significantly attenuated by free radical scavengers (TBAP). Increased lethality was also observed in primary CD34(+) cells from patients with CML, but not in normal CD34(+) cells. Finally, minimally active vorinostat or SNDX275 doses markedly increased KW2449 antitumor effects and significantly prolonged the survival of murine xenografts bearing IM-resistant ALL cells (BV173/E255K). CONCLUSIONS: HDACIs increase KW-2449 lethality in Bcr/Abl(+) cells in association with inhibition of Bcr/Abl, generation of ROS, and induction of DNA damage. This strategy preferentially targets primary Bcr/Abl(+) hematopoietic cells and exhibits enhanced in vivo activity. Combining KW-2449 with HDACIs warrants attention in IM-resistant Bcr/Abl(+) leukemias.
KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation.[Pubmed:19541823]
Blood. 2009 Aug 20;114(8):1607-17.
KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G(1) arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G(2)/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as alpha1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.
A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response.[Pubmed:19029442]
Blood. 2009 Apr 23;113(17):3938-46.
Internal tandem duplication mutations of FLT3 (FLT3/ITD mutations) are common in acute myeloid leukemia (AML) and confer a poor prognosis. This would suggest that FLT3 is an ideal therapeutic target, but FLT3 targeted therapy has produced only modest benefits in clinical trials. Due to technical obstacles, the assessment of target inhibition in patients treated with FLT3 inhibitors has been limited and generally only qualitative. KW-2449 is a novel multitargeted kinase inhibitor that induces cytotoxicity in Molm14 cells (which harbor an FLT3/ITD mutation). The cytotoxic effect occurs primarily at concentrations sufficient to inhibit FLT3 autophosphorylation to less than 20% of its baseline. We report here correlative data from a phase 1 trial of KW-2449, a trial in which typical transient reductions in the peripheral blast counts were observed. Using quantitative measurement of FLT3 inhibition over time in these patients, we confirmed that FLT3 was inhibited, but only transiently to less than 20% of baseline. Our results suggest that the failure to fully inhibit FLT3 in sustained fashion may be an underlying reason for the minimal success of FLT3 inhibitors to date, and stress the importance of confirming in vivo target inhibition when taking a targeted agent into the clinical setting.
