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.
|Source||Clin Cancer Res (2011). Figure 1. KW-2449|
|Method||Assessment of apoptosis|
|Cell Lines||CML cells|
|Incubation Time||72 h|
|Results||KW2449 synergistically enhances the lethality of vorinostat/SNDX275 in CML cells|
|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).
|Incubation time||72 or 48 h|
|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|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO ≥67 mg/mL|
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.
|Related FLT3 Products|
Gilteritinib is a potent FLT3/AXL inhibitor with IC50 of 0.29 nM/0.73 nM, respectively.
AMG 925 is a potent and orally bioavailable dual FLT3/CDK4 inhibitor with IC50 of 1 nM and 3 nM, respectively.
G-749 is a novel and potent FLT3 inhibitor with IC50 of 0.4 nM, 0.6 nM and 1 nM for FLT3 (WT), FLT3 (D835Y), and Mer, respectively, showing lower potency against other tyrosine kinases.
UNC-2025 is a potent and orally bioavailable dual MER/FLT3 inhibitor with IC50 of 0.74 nM and 0.8 nM, respectively, about 20-fold selectivity over Axl and Tyro3.
CGP52421 is a FLT3 inhibitor, which is also an metabolite of midostaurin (PKC412).
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