ASP3026 is a potent ALK (Anaplastic Lymphoma Kinase) inhibitor. ASP3026 inhibited ALK kinase activity and was more selective than crizotinib in a Tyr-kinase panel. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3 and that of 3T3 cells expressing EML4-ALK variant 1, 2 and 3. The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor were determined using high-performance liquid chromatography-tandem mass spectrometry. ASP3026 showed potent anti-tumor effects while crizotinib was ineffective even at 100 mg/gk qd in an EML4-ALK driven tumor model with gatekeeper mutation.
Chem Biol Interact. 2023 Apr 26;379:110516.
ZYY-B-2, a novel ALK inhibitor, overcomes resistance to ceritinib by inhibiting P-gp function and induces apoptosis through mitochondrial pathway in ceritinib-resistant H2228 cells
ASP3026 purchased from AbMole
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Source | Oncotarget (2014). Figure 2. ASP3026 |
| Method | apoptosis assay | |
| Cell Lines | lymphoma cells | |
| Concentrations | 0.5, 1.5, and 2.5 μM | |
| Incubation Time | 48 h | |
| Results | The occurrence of apoptosis after treatment with ASP3026 was biochemically supported by cleavage of caspase 3 and PARP |
| Cell Experiment | |
|---|---|
| Cell lines | NPM-ALK+ ALCL cells Karpas 299, SR-786 and SU-DHL-1 cells |
| Preparation method | MTS assay Cell viability was measured using MTS reagent (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; Promega, Madison, WI). Briefly, 1 × 105 cells were seeded into 96-well plates, and 20 μL of MTS reagent was added to each well and incubated for approximately 2 h at 37°C in 5% CO2. Plates were read at 490 nm. |
| Concentrations | 0.1, 0.5 and 1 μ M |
| Incubation time | 48 or 72 h |
| Animal Experiment | |
|---|---|
| Animal models | Systemic xenograft NPM-ALK+ ALCL model |
| Formulation | 0.5% methylcellulose |
| Dosages | 30 mg/kg daily for 12 weeks |
| Administration | oral gavage |
| Molecular Weight | 580.76 |
| Formula | C29H40N8O3S |
| CAS Number | 1097917-15-1 |
| Solubility (25°C) | DMSO 12 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.
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