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.
|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 models||Systemic xenograft NPM-ALK+ ALCL model|
|Dosages||30 mg/kg daily for 12 weeks|
|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.
The ALK inhibitor ASP3026 eradicates NPM-ALK⁺ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model.
George SK, et al. Oncotarget. 2014 Jul 30;5(14):5750-63. PMID: 25026277.
|Related ALK Products|
Entrectinib (RXDX-101) is an orally bioavailable pan-TrkA/B/C, ROS1 and ALK inhibitor with IC50 ranging between 0.1 and 1.7 nM. Phase 2.
Crizotinib is inhibitor of the c-Met kinase and the NPM-ALK. Crizotinib inhibited cell proliferation in ALK-positive ALCL cells (IC50s=30 nM). Crizotinib is useful in treatment of anaplastic large-cell lymphoma.
Brigatinib (AP26113) is a potent and selective ALK (IC50, 0.6 nM) and ROS1 (IC50, 0.9 nM) inhibitor. It also inhibits ROS1, FLT3, and mutant variants of FLT3 (D835Y) and EGFR with lower potentcy.
ALK-IN-1 is an analog of AP26113 which is a potent and selective ALK inhibitor. It is also an inhibitor of EGFR.
CEP-37440 is a novel potent and selective Dual FAK/ALK inhibitor with IC50 s of 2.3 nM (FAK) and 120 nM(ALK cellular IC50 in 75% human plasma).
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