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 | |
| Concentrations | 0.2–0.6 μM | |
| Incubation Time | 72 h | |
| Results | KW2449 synergistically enhances the lethality of vorinostat/SNDX275 in CML cells |
| 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.) |
| Molecular Weight | 332.4 |
| Formula | C20H20N4O |
| CAS Number | 1000669-72-6 |
| Solubility (25°C) | DMSO 57 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| 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 Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
[2] Sato T, et al. Blood. FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo.
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| GTP-14564
GTP-14564 is a tyrosine kinase inhibitor targeting to internal tandem duplication (ITD) and FLT3. |
| HDAC-IN-63
HDAC-IN-63 is a dual FLT3/HDAC inhibitor (IC50: 0.844 and 30.0 nM for FLT3 and HDAC1 respectively). |
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