LDK378 is a selective small molecule inhibitor of ALK, a target found in metastatic non-small cell lung cancer (NSCLC). LDK378 shows great anti-proliferative activity in Ba/F3-NPM-ALK and Karpas290 cells with IC50 of 26.0 nM and 22.8 nM, compared with IC50 of 319.5 nM and 2477 nM in Ba/F3-Tel-InsR and Ba/F3-WT cells. LDK378 induces a dose-dependent growth inhibition and tumor regression in the Karpas299 and H2228 rat xenograft models, with no body-weight loss. In Phase I trials, LDK378 showed a marked clinical response in 78 patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small cell lung cancer who had progressed during or after crizotinib therapy or had not been previously treated with crizotinib.
|Cell lines||Ba/F3-NPM-ALK, Ba/F3-Tel-InsR, Ba/F3-WT, Karpas299 cells|
|Preparation method||Luciferase-expressing cells are incubated with serial dilutions of LDK378 or DMSO for 2-3 days. Luciferase expression is used as a measure of cell proliferation/survival and is evaluated with the Bright-Glo Luciferase Assay System. IC50 values are generated by using XLFit software.|
|Incubation time||2-3 days|
|Animal models||RNU nude rats bearing the Karpas299/H2228 tumors|
|Formulation||LDK378 (phosphate salt) formulated in 0.5% methylcellulose/0.5% Tween 80|
|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 90 mg/mL
Ethanol 30 mg/mL
|Source||Oncotarget (2015). Figure 2. LDK378|
|Cell Lines||nude mice|
|Incubation Time||21 day|
|Results||There was a significant inhibition of tumor growth in the group with a combination of ceritinib and paclitaxel compared with other groups (P < 0.05)|
|Source||Oncotarget (2015). Figure 1. LDK378|
|Cell Lines||HEK293/ABCB1 and HEK293/ABCG2-R2 cells|
|Incubation Time||48 h|
|Results||Based on the cytotoxicity curves, more than 85% of the cells survived at the concentration of 0.5 μM ceritinib|
Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.
Marsilje TH, et al. J Med Chem. 2013 Jun 26. PMID: 23742252.
|Related ALK Products|
TPX-0005 is a potent ALK/ROS1/TRK inhibitor, with IC50 of 5.3 nM, 1.01 nM, 1.26 nM and 1.08 nM for SRC, WT ALK, ALK G1202R and ALK L1196M, respectively.
LDK378 2Hcl (Ceritinib) is potent inhibitor against ALK with IC50 of 0.2 nM, shows 40- and 35-fold selectivity against IGF-1R and InsR, respectively.
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.
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