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KW-2449

Cat. No. M1815
KW-2449 Structure
Synonym:

KW2449

Size Price Availability Quantity
10mg USD 80 In stock
50mg USD 320 In stock
100mg USD 580 In stock
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Quality Control
Biological Activity

KW-2449 is a multikinase inhibitor of FLT3, ABL, ABL-T315I and Aurora kinase that induces cytotoxicity in Molm14 cells (which harbor an FLT3/ITD mutation). In addition, KW-2449 potently inhibited ABL-T315I, which is associated with IM resistance, with an IC50 value of 4 nM. 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. KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.

Protocol
Cell Experiment
Cell lines K562 and LAMA cells line
Preparation method Assessment of apoptosis
The extent of apoptosis was evaluated by either annexin V-fluorescein isothiocyanate staining (BD Pharmigen) or 7-aminoactinomycin D (Sigma–Aldrich) by flow cytometry as described previously (19, 20).
Concentrations 0.4 μmol/L
Incubation time 72 or 48 h
Animal Experiment
Animal models CBySmn.CB17-Prkdsscid/J (BALB/C) mice (The Jackson Laboratory) BV173/E255K/Luc cl4 cells tumour model
Formulation dissolved in 0.5% methylcellulose 400 solution (Wako)
Dosages 32 mg/kg/d, 5 d/wk
Administration orally (p.o.)
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 332.4
Formula C20H20N4O
CAS Number 1000669-72-6
Purity 99.56%
Solubility DMSO ≥67 mg/mL
Storage at -20°C
References

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.
Nguyen T, et al. Clin Cancer Res. 2011 May 15;17(10):3219-32. PMID: 21474579.

FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo.
Sato T, et al. Blood. 2011 Mar 24;117(12):3286-93. PMID: 21263155.

FLT3-mutant allelic burden and clinical status are predictive of response to FLT3 inhibitors in AML.
Pratz KW, et al. Blood. 2010 Feb 18;115(7):1425-32. PMID: 20007803.

KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation.
Shiotsu Y, et al. Blood. 2009 Aug 20;114(8):1607-17. PMID: 19541823.

A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response.
Pratz KW, et al. Blood. 2009 Apr 23;113(17):3938-46. PMID: 19029442.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: KW-2449, KW2449 supplier, FLT3, inhibitors

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