Cat No.
CEI-0836
Description
LDK378 is potent against ALK with IC50 of 0.2 nM, selectivity against these off-targets is 80-, 70- and 230-fold, respectively. Phase 2.
CAS No.
1032900-25-6
IC50
0.2 nM
Targets
ALK
Chemical Name
2,4-Pyrimidinediamine, 5-chloro-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-N2-[5-methyl-2-(1-methylethoxy)-4-(4-piperidinyl)phenyl]-
M.Wt
558.14
Solubility
DMSO 20 mg/mL; Water <1 mg/mL; Ethanol 3 mg/mL
Storage
2 years -20 centigrade Powder; 2 weeks 4 centigrade in DMSO; 6 months -80 centigrade in DMSO.
In vitro
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.
In vivo
LDK378 is designed to reduce the possibility of forming reactive metabolites and shows undetectable levels of glutathione (GSH) adducts (<1%) in liver microsomes. LDK378 has relatively good metabolic stability, with moderate CYP3A4 (Midazolam substrate) inhibition and hERG inhibition. LDK378 exhibits low plasma clearance in animals (mouse, rat, dog and monkey) compared to liver blood flow, with the oral bioavailability of above 55% in mouse, rat, dog and monkey. LDK378 induces a dose-dependent growth inhibition and tumor regression in the Karpas299 and H2228 rat xenograft models, with no body-weight loss. LDK378 shows no impact on insulin levels or plasma glucose utilization in the mouse upon chronic dosing up to 100 mg/kg.
Features
Does not cross react with c-Met with improved profile in vivo glucose homeostasis over TAE684, may be active in Crizotinib-relapsed tumors.
